
==== Front
Signal Transduct Target Ther
Signal Transduct Target Ther
Signal Transduction and Targeted Therapy
2095-9907
2059-3635
Nature Publishing Group UK London

38057315
1669
10.1038/s41392-023-01669-0
Review Article
Non-coding RNAs expression in SARS-CoV-2 infection: Pathogenesis, clinical significance and therapeutic targets
Liu Xiaoxing 1
Xiong Wandi 23
Ye Maosen 4
Lu Tangsheng 5
Yuan Kai 1
Chang Suhua 1
http://orcid.org/0000-0002-8381-4071
Han Ying 5
Wang Yongxiang wang-yongxiang@hotmail.com

67
Lu Lin linlu@bjmu.edu.cn

125
Bao Yanping baoyp@bjmu.edu.cn

568
1 grid.11135.37 0000 0001 2256 9319 Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), 100191 Beijing, China
2 https://ror.org/02v51f717 grid.11135.37 0000 0001 2256 9319 Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, 100871 Beijing, China
3 https://ror.org/03q648j11 grid.428986.9 0000 0001 0373 6302 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, 570228 Haikou, China
4 grid.419010.d 0000 0004 1792 7072 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, 650204 Kunming, Yunnan China
5 https://ror.org/02v51f717 grid.11135.37 0000 0001 2256 9319 National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191 China
6 https://ror.org/05jb9pq57 grid.410587.f Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, 250117 Jinan, Shandong China
7 grid.410638.8 0000 0000 8910 6733 Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong China
8 https://ror.org/02v51f717 grid.11135.37 0000 0001 2256 9319 School of Public Health, Peking University, 100191 Beijing, China
6 12 2023
6 12 2023
2023
8 4419 12 2022
12 9 2023
28 9 2023
© The Author(s) 2023
2023
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The coronavirus disease 2019 (COVID-19) pandemic has been looming globally for three years, yet the diagnostic and treatment methods for COVID-19 are still undergoing extensive exploration, which holds paramount importance in mitigating future epidemics. Host non-coding RNAs (ncRNAs) display aberrations in the context of COVID-19. Specifically, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) exhibit a close association with viral infection and disease progression. In this comprehensive review, an overview was presented of the expression profiles of host ncRNAs following SARS-CoV-2 invasion and of the potential functions in COVID-19 development, encompassing viral invasion, replication, immune response, and multiorgan deficits which include respiratory system, cardiac system, central nervous system, peripheral nervous system as well as long COVID. Furthermore, we provide an overview of several promising host ncRNA biomarkers for diverse clinical scenarios related to COVID-19, such as stratification biomarkers, prognostic biomarkers, and predictive biomarkers for treatment response. In addition, we also discuss the therapeutic potential of ncRNAs for COVID-19, presenting ncRNA-based strategies to facilitate the development of novel treatments. Through an in-depth analysis of the interplay between ncRNA and COVID-19 combined with our bioinformatic analysis, we hope to offer valuable insights into the stratification, prognosis, and treatment of COVID-19.

Subject terms

Epigenetics analysis
Predictive markers
issue-copyright-statement© West China Hospital, Sichuan University 2023
==== Body
pmcIntroduction

It is still a public health concern of the coronavirus disease 2019 (COVID-19) pandemic worldwide, three years after its outbreak. Until July 12, 2023, the global cumulative number of COVID-19 confirmed cases rose to 767.7 million and the cumulative death increased to nearly seven million, indicating that we must remain vigilant against COVID-19. Furthermore, the pandemic has inflicted a substantial attack to the global economy; most countries encountered negative gross domestic product rates in 2020 based on estimations by the World Bank and International Monetary Fund.1 The World Economic Situation and Prospects, an United Nations’ latest report, suggests that prospects for a robust global economic recovery remain bleak due to persistent repercussions of the COVID-19 pandemic.2 Therefore, it is still critical to focus attention on COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded positive ribonucleic acid (RNA) virus, is the causative agent, and multiple variants have emerged, ranging from alpha to omicron.3 SARS-CoV-2, belonging to the Sarbecovirus subgenus of betacoronavirus, possesses a genomic RNA with an average size of 26-32 kilobase and an outer shield composed of envelope (E), membrane (M), and spike (S) proteins.4 This virus primarily invades host cells through a combination with its receptor protein, angiotensin-converting enzyme 2 (ACE2), leading to immune system damage, and increased inflammatory factors release and even cytokine storms.4,5 The COVID-19 disease presents with a diverse kind of clinical symptoms affecting multiple systems, including respiratory, neuropsychiatric, cardiovascular, gastrointestinal, musculoskeletal and endocrine systems. It is common overserving fever, cough, shortness of breath and general malaise in these patients.6,7 In addition, a significant proportion of recovered individuals experience long-term symptoms referred to as “long COVID”, which is defined by the World Health Organization (WHO) as lasting for at least 2 months and cannot be explained by an alternative diagnosis occurring usually 3 months from the onset of COVID-19. These long-term symptoms may include fatigue, muscular weakness, dyspnea and neuropsychiatric manifestations such as depression, anxiety and cognitive deficits.8,9 Despite extensive global efforts dedicated to investigating SARS-CoV-2, our current understanding of its pathogenesis, including clinical progression and effective treatments, remains in progress.

Non-coding RNAs (ncRNAs) serve as a critical regulator of the genome, providing an insight to viral pathogenesis and thus to developing antiviral therapeutics. NcRNAs constitute approximately 90% of RNAs in the human genome and participate in both physiological and pathological processes.10 Among these ncRNAs, the most studied types include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs).11 MiRNAs are a type of short ncRNAs that mediate genes and subsequent signaling by regulating the expression of other RNAs, especially messenger RNAs (mRNAs). In contrast, lncRNAs, a kind of ncRNAs with more than 200 nucleotides, can modulate the transcription of neighboring or distant genes, as well as regulate chromatin biology.12 The third major class of ncRNAs is circRNAs, a novel class with a closed continuous loop structure. Studies about the circRNAs function is still in progress, while many research have found that circRNAs can function as miRNA sponges, even binding multiple miRNA molecules and inhibit their roles.13 In a short brief, the ways in which these ncRNAs modulate gene expression can be summarized as follows (Fig. 1): (1) miRNA can target the mRNA to regulate the cascades; (2) some lncRNAs can make an impact on mRNA stability and manage the translation of related mRNAs in the cytoplasm; (3) some ncRNAs, such as lncRNAs and circRNAs, can function as scaffolds that enable interactions with multiple proteins; (4) some abundant circRNAs can bind miRNAs in the cytoplasm, acting as miRNA sponges to prevent miRNAs from binding their target mRNAs; and (5) some lncRNAs can recruit proteins to mRNAs and mediate mRNA decay.14–16 It is currently believed that ncRNAs may also play regulatory roles in the pathogenesis of COVID-19.Fig. 1 The main ways for ncRNAs in modulating gene expression in SARS-CoV-2-infected cells. The main mechanisms of the ways in which ncRNAs regulate gene expression are shown: a transcriptional regulation, b chromatin biology, c translational regulation, d scaffolding, e mRNA sponge, and f mRNA decay. Biorender was used to generate this figure

What is noteworthy is that both humans and viruses can produce ncRNAs, and virus-encoded ncRNAs can manipulate the host cell machinery to facilitate viral genome expression and protein production, as well as inhibit antiviral pathways.17 Extensive reviews have summarized the primary functions of virus-encoded miRNAs/lncRNAs/circRNAs, including regulating viral gene expression for latency control or activation transmission, and modulating the host immune system to create a favorable intracellular environment for viral persistence.18–20 Currently, virus-encoded ncRNAs are mainly identified in deoxyribonucleic acid (DNA) virus infections, while few originate from RNA viruses due to limited accessibility of host ncRNA biogenesis machinery in nuclei for RNA virus.17 However, some investigations have detected the virus-encoded ncRNAs expression after infection with various coronaviruses such as Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-1 as well as SARS-CoV-2. For instance, Cai et al. discovered 3437 circRNAs derived from SARS-CoV-2 in 2020 which were associated with cholesterol metabolism processes and cellular responses to oxidative stress.21 Similarly, 40 viral miRNAs derived from the SARS-CoV-2 genome was identified, which mostly targeted genes of signaling pathway, epigenetics factors, tumor suppressors, transcription factors, and various kinases.22 Despite the significance of virus-encoded ncRNAs in modulating viral diseases and their potential clinical applications, the mechanisms underlying these ncRNAs, particularly those encoded by RNA viruses, remain uncertain. Therefore, we did not delve further into this topic in our review, which may represent a missing piece for comprehending the interplay between hosts and viruses.

Given the pivotal role of host ncRNAs in viral pathogenesis, there is promising potential to develop early identification, differentiation predictor, and efficacious interventions based on ncRNAs for managing the ongoing COVID-19 pandemic and preventing long-term sequelae. This review is specifically aimed at elucidating the expression profiles and functions of host ncRNAs (miRNAs, lncRNAs, and circRNAs) in SARS-CoV-2 pathogenesis, from viral invasion and replication to multiorgan deficits, and even to long COVID. Additionally, we provide a comprehensive overview of current research investigating the efficacy of ncRNA-based biomarkers and therapeutic approaches in relation to COVID-19 and long COVID.

Dysregulated expression of the host ncRNAs in COVID-19

In the present, the main approaches for measuring ncRNAs expression can be divided into two types.23 One method with low throughput is represented by quantitative real-time polymerase chain reaction (RT-qPCR), northern blot, and in situ hybridization. Among these, RT-qPCR is due to its inexpensive and sensitive properties,24 now widely employed in clinical and basic research for detecting single or a small number of ncRNAs.25 Moreover, novel techniques have been developed based on the conventional PCR method, such as droplet-based digital PCR (ddPCR), which primarily relies on limited dilution, end-point PCR, and Poisson statistics.26 DdPCR offers several advantages including remarkable sensitivity and specificity, absolute quantification without a standard curve, excellent reproducibility, and high efficiency, making it a valuable addition to measuring the ncRNAs.27 The other type is a high-throughput technique such as RNA sequencing and microarrays. Compared with the microarrays which mainly pick up the known targets, the RNA sequencing can generate comprehensive and high-quality data that reveals unknown transcripts.28 Recently, the developing single-cell RNA sequencing and spatial transcriptomics sequencing technologies have made it possible that the RNAs expression in individual cells can be accurately distinguished within their native environment, exhibiting higher spatial specificity.29

Numerous studies have been conducted to measure the differentially expressed ncRNAs (DEncRNAs) in the host after SARS-CoV-2 infection through RT-qPCR, sequencing or microarrays (Table 1). Host miRNAs have garnered significant attention, with a plethora of published clinical reports investigating their presence in samples from individuals diagnosed with COVID-19. Despite the limited research on the expression profile of lncRNAs and circRNAs in the context of COVID-19, findings have revealed significant alterations in hundreds or even thousands of these ncRNAs among COVID-19 individuals. The majority of samples used to extract host ncRNAs were derived from various types of blood samples, including peripheral blood, peripheral venous blood, serum, plasma, red blood cell-depleted peripheral blood, and peripheral blood mononuclear cells (PBMCs).17,30–34 In addition, other tissues, such as nasopharyngeal samples, saliva, urine, bone, cerebrospinal fluid (CSF), and post-mortem lung biopsies, were also analyzed.35–40 Moreover, the expression profile of some ncRNAs can present dynamic changes over time, from the acute phase to post-acute, and even to the convalescence stage.41,42 In the following parts, we introduce the expression profiles of host miRNAs/lncRNAs/circRNAs after SARS-CoV-2 infection, and discuss the possible ways for SARS-CoV-2 to modulate the host ncRNAs expression.Table 1 Clinical research on the detection of host ncRNAs expression in samples from people with SARS-CoV-2 infection

No.	Reference	Country	Participants	Sample size	Mean age	Sex (female, %)	Tissue type	Method	COVID-19 severity	Time for cases recruitment	Time of collecting samples	ncRNAs type	
1	Abbasi-Kolli et al.41	Germany	COVID-19 cases	50	38.1	25, 50.00%	PBMCs	RT-PCR	/	2021.6-7	At acute infection, 6-7 weeks after the acute phase	miRNAs

lncRNAs

	
Health control	50	37.2	25, 50.00%						
2	Abdolahi et al.217	Iran	COVID-19 cases	30	59.67	10, 33.30%	PB	RT-qPCR	/	2020.5-8	At admission and discharge	miRNAs	
Health control	18	32.70	11, 61.10%			
3	Agwa et al.32	Egypt	COVID-19 cases	100	32.80	44, 44.00%	Serum	RT-qPCR	Mild, severe	2020	At admission	miRNAs	
			Health control	100	34.30	48, 48.00%						lncRNAs	
4	Akula et al.187	USA	COVID-19 cases	12	47.80	6, 50.00%	Plasma	NGS, RT-qPCR	Moderate-to-severe	/	/	miRNAs	
			Health control	8	46.00	5, 62.50%							
5	Ayeldeen et al.167	Egypt	COVID-19 cases	200	58.96	98, 49.00%	Serum	RT-qPCR	Moderate, severe	/	/	miRNAs

lncRNAs

	
			Health control	80								
6	Aznaourova et al.57	Germany	COVID-19 cases	11	70.36	3, 27.27%	PBMCs	scRNA-seq	Severe	/	/	lncRNAs	
			Health control	8	57.50	4, 50.00%							
7	Bagheri-Hosseinabadi et al.30	Iran	COVID-19 cases	33	62.40	20, 60.60%	PB	RT-qPCR	/	/	At admission	miRNAs	
			Health control	29	56.60	20, 69.00%							
8	Centa et al.40	Brazil	COVID-19 non-survivors	9	73.40	3, 33.30%	FFPE post-mortem lung biopsies	RT-qPCR	/	/	/	miRNAs	
			Patients who died due to other causes	10	42.30	3, 30.00%						
9	Cheng et al.54	China	COVID-19 cases	29	Severe:74.00; NS: 69.14	/	PBMCs	NGS	Mild/moderate, severe	2020.3-4	/	miRNAs

lncRNAs

	
			Health control	10	/	/							
10	de Gonzalo-Calvo et al.88	Spain	COVID-19 cases	79	68.00	35, 44.30%	Plasma	RT-qPCR	/	2020.3-5	At admission	miRNAs	
11	Demiray et al.218	Turkey	COVID-19 cases	40	55.00	17, 42.50%	Serum	RT-qPCR	Mild, severe	2020.3-4	/	miRNAs	
			Health control	10	36.00	6, 60.00%							
12	Devados et al.113	USA	COVID-19 cases	20	/	7, 35.00%	Nasopharyngeal swabs	/	Symptomatic	/	/	lncRNAs	
13	Donyavi et al.45	Iran	COVID-19 cases	18	38.20	9, 50.00%	PBMCs	RT-qPCR	/	2020.4-7	At the acute period and the recovery period	miRNAs	
			Health control	15	36.60	7, 47.70%						
14	Duecker et al.44	Germany	COVID-19 cases	21	72.00	4, 19.00%	Whole blood	NGS	Moderate, severe	/	At the acute period (day 0–3) and in the later course of the disease (>7 days)	miRNAs	
			Health control	8	68.00	3, 37.50%						
15	Farr et al.52	Australia	COVID-19 cases	10	53.50	6, 60.00%	Plasma	NGS; RT-qPCR	Moderate. Severe	2020.2-4	After 2–15 days (average 8 days) of disease onset	miRNAs	
			Health control	10	53.00	6, 60.00%						
16	Fayyad-Kazan et al.219	Lebanon	COVID-19 cases	12	/	/	Plasma	MiRCURY LNA miRNA miRNome qPCR	Mild, moderate, severe	/	At the time of diagnosis	miRNAs	
			Health control	12	/	/						
17	Fernández-Pato et al.43	Spain	COVID-19 cases	96	Mild: 63.40; moderate: 59.40; severe: 66.20	43, 44.80%	Plasma	NGS	Asymptomatic/mild, moderate, severe	2020.3-8	At hospital entry or within the first days after hospitalization	miRNAs	
			Health control	13	66.70	6, 46.20%						
18	Firoozi et al.114	Iran	COVID-19 cases	100	/	43, 43.00%	PBMCs	RT-qPCR	Asymptomatic, symptomatic	/	/	miRNAs

circRNAs

	
			Health control	50	43.16	23, 46.00%							
19	Gambardella et al.220	USA	COVID-19 with or without CBV	321	61.90	145, 45.20%	EC-EVs	/	/	2020.10-2021.4	/	miRNAs	
			Patients with CBV	37	65.37	15, 40.50%						
			Healthy control	57	59.4	28, 49.1%						
20	Garg et al.46	Germany	COVID-19 cases	38	DC: 59.00; VC: 59.50	7, 18.40%	Serum	RT-qPCR	Severe	/	/	miRNAs	
			Influenza-ARDS patients	13	56.00	2, 15.40%							
			Health control	15	31.00	1, 6.70%							
21	Giuliani et al.47	Italy	COVID-19 cases	128	DC: 75.40; VC: 86.50	83, 64.80%	Serum	NGS	/	2020.3-6	At admission	miRNAs	
22	Grehl et al.221	Germany	COVID-19 cases	10	/	6, 60.00%	Plasma	NGS	Mild, severe	2020.3-8	Within the first 3 weeks after symptom onset	miRNAs	
			Patients with bacterial pneumonia	1	/	1, 100%						
			Health control	1	/	1, 100%						
23	Gutmann et al.49	UK	COVID-19 cases	97	/	36, 37.10%	Plasma	RT-qPCR; NGS	Mild, moderate, severe	2020.5-12	Mild/moderate: at admission; severe: within ICU admission	miRNAs	
			Health control	11	40.00	6, 54.50%						
24	Haroun et al.160	Egypt	COVID-19 cases	150	49.43	61, 40.70%	Plasma	RT-qPCR	Moderate, severe	/	At admission	miRNAs	
			Health control	50	45.80	/							
25	Keikha et al.176	Iran	COVID-19 cases	103	/	53, 51.50%	Serum	RT-qPCR	/	2020.12-2021.3	At admission	miRNAs	
			Health control	20	/	/							
26	Li CX et al.222	China	COVID-19 cases	10	44.90	6, 60.00%	PB	NGS	Mild or moderate	2020.2-3	Within 1 week after diagnosis	miRNAs	
			Health control	4	44.75	2, 50.00%				
27	Li CX et al.53	China	COVID-19 cases	10	44.90	6, 60.00%	PB	NGS	/	2020.2-3	/	miRNAs	
			Health control	4	34.75	3, 75.00%					lncRNAs	
28	Liu et al.33	China	COVID-19 cases	10	/	5, 50.00%	Red blood cell-depleted peripheral blood	RT-qPCR	Moderate, severe	2020.1–3	/	miRNAs	
			Health control	4	/	/						
29	Loretelli et al.146	Italy	COVID-19 cases	57	54.70	29, 50.88%	PBMCs	qPCR	/	2020.3-10	/	miRNAs	
			Post-COVID-19 cases	39	55.30	10, 25,64%						
			Health control	43	47.30	25, 58.14%						
30	Martı´nez-Fleta et al.223	Spain	COVID-19 cases	123	DC: 59.50; VC: 64.00	65, 52.80%	Plasma	RT-qPCR	Mild, severe	2020.3-4	Within 5 days upon admission	miRNAs	
			CAP adult patients	33	Dc: 62.00; vc: 66.50	15, 45.50%							
31	McDonald et al.37	USA	COVID-19 cases	50	/	/	Serum, nasopharyngeal, urine	/	/	2020.3-5	/	miRNAs	
			Negative control	25	/	/						
			Common cold coronavirus	6	/	/						
			Coronavirus NL63	6	/	/							
			Healthy control	11	/	/							
32	Meidert et al.224	Germany	COVID-19 cases	30	COVID-19 pneumonia: 63.00; COVID-19 ARDS: 65.00	4, 13.30%	EVs	NGS, RT-qPCR	/	2020.3-4	At admission	miRNAs	
			Health control	18	35.00	7, 38.90%					
			CAP	12	71.00	4, 33.30%					
33	Mi et al.38	China	COVID-19 cases with fracture	30	/	/	Muscle, bone, and bone marrow specimens	RT-qPCR	/	/	At the time of diagnosis	miRNAs	
			Fracture patients	50	55.90	25, 50%					
34	Parray et al.31	Sweden	COVID-19 cases	29	Asymptomatic: 54.50; mild: 49.60; severe: 58.22	0, 0%	PVB	Affymetrix GeneChip miRNA 4.0 array	Severe, mild, and asymptomatic	/	At the time of diagnosis prior to isolation, or at admission	miRNAs	
35	Pimenta et al.181	Brazil	COVID-19 cases	72	/	/	Saliva	RT-qPCR	symptomatic clinical conditions with no indication of hospitalization, symptomatic clinical conditions with respiratory disorders, severe	2020.6-10	At the time of diagnosis	miRNAs	
			Health control	39	/	/							
36	Reinhold et al.39	Germany	COVID-19 cases	38	68.60	10, 26.32%	Serum, CSF	NGS	/	/	/	lncRNAs

circRNAs

	
			HSVE patients	10	54.60	4, 40.00%							
			Patients with non-inflammatory, non-neurodegenerative neurological diseases	28	58.70	11, 39.29%							
37	Rodrigues et al.36	Brazil	COVID-19 cases	18	41.50	/	Nasopharyngeal swab, saliva	RT-qPCR	/	/	/	lncRNAs	
			Healthy control	23	40.00	/						
38	Rombauts et al.55	Spain	COVID-19 cases	60	63.00	23, 38.30%	PB	NGS	with ARDS, without ARDS	202.3-7	At admission and on day 7 of hospital admission	lncRNAs	
39	Srivastava et al.225	India	COVID-19 cases	17	/	/	PB	NGS	Moderate, severe	/	/	miRNAs	
			COVID-19 non-survivors	16	/	/						
			Healthy control	10	/	/						
40	Taheri et al.161	Tehran	COVID-19 cases	91	57.18	38, 41.8%	PB	RT-qPCR	ICU, non-ICU	2020.3-4	At admission	lncRNAs	
			Healthy control	91	/	39, 42.9%							
41	Tang et al.50	China	COVID-19 cases	12	/	9, 75.00%	Red blood cell-depleted whole blood	NGS	Moderate, severe	/	At admission	miRNAs	
			Healthy control	4	/	2, 50.00%				lncRNAs	
42	Wang et al.226	China	COVID-19 cases	37	53.90	11, 29.70%	Whole blood	NGS	Mild, severe	2020.1-2	At admission	miRNAs	
			Healthy control	8	45.80	1, 12.50%						lncRNAs	
43	Wilson et al.48	UK	COVID-19 cases	58	63.00	22, 37.90%	Plasma	NGS	Mild, moderate, severe	2020.4-10	At admission	miRNAs	
			Healthy control	/	/	/							
44	Wu J et al.51	China	COVID-19 cases	29	47.45	12, 41.40%	Plasma	RT-qPCR	Mild, severe	2020.1-5	At admission	miRNAs	
			Healthy control	29	48.34	15, 51.70%							
45	Wu WZ et al.35	China	COVID-19 cases	4	54.30	/	Nasopharyngeal swabs	NGS	/	2020.4	At admission	miRNAs	
			Healthy control	4	50.50	/					
46	Wu YP et al.34	China	Recurrent COVID-19 cases	3	/	/	Whole blood	/	/	/	At admission	lncRNAs

circRNAs

	
			Healthy control	3	/	/							
47	Yang et al.227	China	COVID-19 cases	5	/	/	Whole blood	/	/	2020.1-2	At admission	lncRNAs	
			Healthy control	3	/	/							
48	Zhang et al.228	China	COVID-19 cases	39	/	17, 43.59%	PBMCs	Arraystar Human LncRNA Microarray V5.0	Mild, severe	2020.1-2	/	lncRNAs	
			Healthy control	5	/	/						
49	Zheng et al.42	China	COVID-19 cases	18	/	7, 38.90%	PVB	NGS	Mild, moderate, severe	2020.1-4	At the time of treatment, convalescence stage, rehabilitation stage	miRNAs

lncRNAs

	
ARDS associated acute respiratory distress syndrome, CAP community-acquired pneumonia, CBV cerebrovascular, CSF cerebrospinal fluid, DC discovery cohort, EC-EVs endothelial cells-extracellular vesicles, EVs extracellular vesicles, FC fold change, FFPE formalin-fixed paraffin-embedded, HSVE herpes simplex virus type 1 encephalitis, NGS next-generation sequencing, NS non-severe, PB peripheral blood, PBMCs peripheral blood mononuclear cells, PVB peripheral venous blood, RT-qPCR quantitative real-time polymerase chain reaction, scRNA-seq single-cell RNA sequencing, VC validation cohort

SARS-CoV-2-associated DEncRNAs

miRNAs

A number of investigations have reported that the host miRNAs expression is altered in COVID-19 individuals in contrast to healthy controls, suggesting potential involvement of miRNAs in the COVID-19 pathogenesis.43 In addition, the host miRNAs expression can be influenced by disease severity, as evidenced by comparisons between asymptomatic/mild and symptomatic patients or among mild, moderate, and severe cases, highlighting the remarkable potential of miRNAs in distinguishing the COVID-19 severity through demonstrating the diverse landscape of miRNAs in patients with varying disease severities.31 In addition, the temporal sensitivity of the differentially expressed miRNAs (DEmiRNAs) profile in the context of COVID-19 is evident. On one hand, it exhibits dynamic changes within a few days of disease onset, even changing between the acute stage (within 3 days) and later period (>7 days), thereby indicating the potential to predict symptoms characterized by rapid onset after SARS-CoV-2 infection.44,45 On a broader temporal scale encompassing treatment, convalescence, and rehabilitation stages, the expression pattern of DEmiRNAs which resulted from SARS-CoV-2 infection also demonstrates discernibility.42 Furthermore, SARS-CoV-2 infection may lead to a distinct expression profile of host miRNAs differentiated from those infected with other viruses. Compared to patients with influenza-associated acute respiratory distress syndrome (influenza-ARDS), three upregulated miRNAs in the serum were identified in severe COVID-19 patients, contributing to deciphering the unique pathogenesis of SARS-CoV-2.46

Among the myriad of dysregulated miRNAs, certain ones have undergone additional validation in diverse populations or through alternative methodologies.46–48 Further, the abundance of PCR or sequencing data facilitated a comprehensive analysis of the expression profile of DEmiRNAs in COVID-19 patients. This enabled us to identify DEmiRNAs that were repeatedly measured across multiple studies and compare their expression patterns among healthy controls, non-severe COVID-19 patients, and severe cases (Supplementary Tables S1–3). Notably, certain miRNAs such as miR-1246 and miR-106b-5p exhibited consistent differential expression across various studies, providing further validation for the impact exerted by SARS-CoV-2 on host miRNA landscape.43,49–52

lncRNAs

Differentially expressed lncRNAs (DElncRNAs) have been recognized in COVID-19 patients with varying disease severities in comparison with healthy controls, as well as among COVID-19 cases with different disease severities, indicating the potential involvement of lncRNAs in the pathogenesis of this disease.53,54 The expression of host lncRNAs also exhibited temporal sensitivity, either within an acute time frame (e.g., from admission to 7 days later) or over a longer progression period (e.g., during treatment, convalescence, and rehabilitation).42,55 Moreover, DElncRNAs can be detected in the recurrent COVID-19 cases, evidenced by that nearly one thousand DElncRNAs were identified in the recurrent COVID-19 patients compared with the healthy controls.34 However, further investigations are worthy to determine whether there exist differences in lncRNAs expression between individuals with a single SARS-CoV-2 infection and those experiencing reinfection, as the number of infections may increase the risk and disease burden, suggesting potential underlying distinctions.56

Insufficient research has been conducted to validate the expression profile of lncRNAs in COVID-19 cases, despite the identification of DElncRNAs at a cellular level. There was a study using single-cell RNA sequencing showing the DElncRNAs in the blood leukocytes in severe COVID-19 cases in comparison with the healthy control, revealing the possible involvement of lncRNAs in the disease development at a much finer spatial scale.57

circRNAs

The current research on differentially expressed circRNAs (DEcircRNAs) in COVID-19 is limited, yet it may offer valuable insights into the DEcircRNAs following SARS-CoV-2 infection and their presence across various samples from COVID-19 patients. In the human lung epithelial cells infected with SARS-CoV-2, more than five thousand circRNAs at various genomic location were identified via genome-wide dynamic analysis.58 In addition, in the whole-blood sample from recurrent COVID-19 cases, DEcircRNAs were also identified compared to the healthy control.34 The aforementioned investigations suggest that the SARS-CoV-2 infection can disrupt the expression of host circRNAs in blood, while a consistent dysregulation has also been observed in the CSF, evidenced by a differential expression profile of circRNAs identified in the CSF compared among COVID-19 case, healthy controls, and cases with neurological disease.39 Considering the tissue- and cell-specificity of the circRNAs expression, whether there is an overlap or difference in the types of DEcircRNAs between the neural cells and blood cells also needs more investigations for deeper understanding the systemic effects of SARS-CoV-2, such as using the single-cell RNA sequencing and spatial transcriptomics sequencing.

Ways for SARS-CoV-2 to alter host ncRNAs expression

Numerous reviews have provided detailed explanations on the biogenesis of host miRNAs/lncRNAs/circRNAs.10,12,59,60 Most host miRNAs are generated through the canonical pathway, which involves transcription by RNA polymerase II or III and maturation via endonucleolytic processing. In addition, some miRNAs can be produced through noncanonical pathways where they are transcribed from short hairpin introns.11 The biogenesis of lncRNAs occurs in the nucleus and originates from the lncRNA genes. Depending on the canonical pathway, lncRNA species are transcribed by polymerase II or III and mature into transcripts.12 While the mechanism of circRNA biogenesis remains unclear, some studies have shown that it also relies on the canonical splicing machinery and most circRNAs are transcribed from known protein-coding regions.60

Following SARS-CoV-2 infection, there are differential expressions of massive host miRNAs, lncRNAs, and circRNAs, indicating that the virus invasion influences ncRNAs expression. However, the mechanisms by which the virus affects host ncRNA expression remain poorly understood due to challenges in defining boundaries between viral factors and host antiviral responses that can result in changes to ncRNA expression.61 Nevertheless, some reports suggest that viruses can directly target specific subsets of ncRNAs or impact global levels of ncRNA expression by influencing various aspects of host ncRNA biogenesis such as transcription, Dicer processing, and export.62 In a study involving SARS-CoV infected cells, a competing endogenous RNAs (ceRNAs) network was identified.63 Among these, the involvement of one mRNA antiviral innate immune response receptor RIG-1 (Ddx58) in the processes of mRNA splicing and miRNA biogenesis results in reprogramming of miRNA splicing and decreased miRNA expression when it is upregulated. Although this study suggests a potential mechanism for SARS-CoV-2 disruption of host ncRNAs through regulating certain key components involved in the miRNA splicing, it is likely that the actual mechanisms are more intricate. In 2023, Garnier et al. found no significant changes in nasopharyngeal swab specimens between COVID-19 patients and controls nor between severe and non-severe cases regarding the miRNA expression levels of several key proteins involved in miRNA biogenesis including protein argonaute-2 (AGO2), endoribonuclease dicer (DICER1), DiGeorge syndrome critical region 8 (DGCR8), drosha ribonuclease III (DROSHA), and Exportin-5.64 Consistently, in vitro experiments using normal human bronchial epithelial (NHBE) and Calu-3 cells invaded by SARS-CoV-2 also exhibited no alterations in these mRNA expressions. These findings suggest that SARS-CoV-2 infection had no effect on the mRNAs expression of key genes associated with miRNA biogenesis. Further investigations are warranted to elucidate the mechanisms by which SARS-CoV-2 induces alterations in host DEncRNAs expression.

The roles of ncRNAs in COVID-19

The COVID-19 pathogenesis initiates with the invasion of SARS-CoV-2. In the early stages of infection, the viral S protein specifically binds to ACE2 receptors present in nasal and bronchial epithelial cells as well as pneumocytes. Mostly utilizing type 2 transmembrane serine protease (TMPRSS2) within these targeted cells, the virus gains entry through endocytosis into host cells.65 Subsequently, it manipulates the host cell machinery to replicate its RNA and assemble additional virions, leading to an escalation in viral copy numbers within the lower respiratory tract.6 Concurrently, infected cells and alveolar macrophages release inflammatory molecules while lymphocytes, monocytes, and neutrophils are recruited. In addition, lymphopoiesis impairment also occurs alongside increased cell apoptosis. During later stage, accelerated viral replication allows SARS-CoV-2 to invade pulmonary capillary endothelial cells, which intensifies inflammation and disrupts endothelial barriers. Furthermore, pulmonary edema can fill alveolar spaces, resembling early-phase ARDS symptoms.66

The development of viral sepsis, which may subsequently lead to multiorgan dysfunction, is a matter of greater concern. Severe lung injury, such as ARDS, represents the primary complication induced by SARS-CoV-2. It has been observed that 15–30% of hospitalized COVID-19 individuals will progress to develop COVID-19-associated ARDS.67 In addition, a range of complications have been demonstrated, including thrombotic events, myocardial dysfunction, and arrhythmia, as well as neuropsychiatric disorders.68 Despite the unclear mechanisms underlying these complications in the context of COVID-19, current perspectives on the pathophysiology of multiorgan failure following SARS-CoV-2 infection primarily focus on direct viral tissue damage and dysregulated host responses induced by the virus.68

Many studies have demonstrated that host ncRNAs exhibit differential expression patterns following SARS-CoV-2 infection but also play a crucial role in various aspects of its pathogenesis. Investigating the functions of ncRNAs in this process can significantly facilitate our understanding of the interplay between the SARS-CoV-2 and host. In the subsequent section, we present some prominent examples of host ncRNAs which have been identified with wet-lab or bioinformatic analysis in the context of COVID-19 (Supplementary Table S4), providing a discussion about how host ncRNAs contribute to COVID-19 pathogenesis through an intricate interplay via direct or indirect action and anti- or pro-viral effects, including viral invasion, replication, immune response modulation, multiorgan deficits as well as long COVID (Fig. 2).Fig. 2 The functions of host ncRNAs in the pathogenesis of COVID-19 and representative ncRNAs. a Possible COVID-19 disease course is depicted as differentially colored curves of disease severity over time.216 b During the progression of this disease, viral invasion serves as the initial step. Following cleavage of the S protein into S1 and S2 subunits by furin in viral producer cells, the SARS-CoV-2 virus can effectively bind to the ACE2 receptor. Subsequent cleavage occurs either through TMPRSS2 or via endocytosis into the endolysosome. Upon entry into the cytoplasm, it undergoes replication to generate multiple copies for dissemination within the host organism. This is accompanied by translation of viral proteins or polypeptides, assembly, and eventual release into extracellular spaces. The released virus can undergo further reorganization, triggering release of inflammatory signaling molecules from infected cells and alveolar macrophages, while also recruiting T cells, monocytes, and neutrophils. Disease exacerbation leads to increased fluid accumulation in alveolar spaces and potentially cytokine storms that induce hyperinflammation. In late stages of illness, some patients may exhibit acute or persistent multiorgan deficits involving organs such as the brain, lungs, and heart. c In the context of COVID-19, several host miRNAs/lncRNAs/circRNAs have been identified through wet-lab experiments or bioinformatic analysis, elucidating their roles in various aspects of COVID-19 pathogenesis, encompassing viral invasion, replication, immune response modulation, multiorgan failure and long COVID. Biorender was used to generate this figure

Impact on SARS-CoV-2 invasion

The invasion of SARS-CoV-2 into target cells involves more than just the interaction between the S protein and its receptor ACE2. The crucial step for virus is to enter the cellular membrane and reach the cytoplasm of targeted cells. To overcome the inherent repulsion between the virus and cell membrane, the S protein must transition into a metastable state (a state prone to transformation to a lower-energy state) before membrane fusion.4 Unlike SARS-CoV which relies on protease cleavage in target cells for this transition, in SARS-CoV-2 cleavage of the S protein occurs in two steps - first by furin in virus-producer cells (cleaving the S protein into S1 and S2 subunit) and then by proteases in target cells (cleaving at the S2 subunit). During the second cleavage, there are two routines utilized by SARS-CoV-2: (1) one dependent on TMPRSS2 located on plasma membranes of target cells and (2) the other relying on cathepsin L located within endolysosome of target cells.4 In host cells co-expressing ACE2 and TMPRSS2, TMPRSS2 is responsible for cleavage of the S2 subunit, followed by ACE2-mediated endocytosis that facilitates viral RNA release into the cytoplasm for replication and uncoating.69,70 However, in cases of inadequate TMPRSS2 expression or absence of virus-ACE2 complex interaction with TMPRSS2, SARS-CoV-2 can be internalized through endocytosis into the endolysosome where cathepsin L cleaves at the S2 subunit, leading to membrane fusion and subsequent viral RNA release.71,72

Despite the evidence from wet-lab about the role of host ncRNAs in regulating the SARS-CoV-2 invasion are still scant, some bioinformatics results indicate that some miRNAs and lncRNAs may modulate the entry process via targeting the furin, ACE2 and TMPRSS2.

Furin

Furin is a type I transmembrane protein that serves as a proprotein convertase, ubiquitously expressed in pulmonary, hepatic, and intestinal tissues.73 In the context of COVID-19, furin-mediated cleavage of the S1/S2 boundary is essential for virus-induced membrane fusion. This unique feature differentiates SARS-CoV-2 from other Sarbecovirus and enables zoonotic transfer to humans.74 A mutant SARS-CoV-2, which was lack of the furin cleavage site, exhibited reduced S protein processing in infected cells compared to parental SARS-CoV-2.75 Although direct experimental evidence on the role of host ncRNAs in modulating furin after SARS-CoV-2 infection is lacking, a bioinformatics study predicted that some host DEmiRNAs from infected cells can target FURIN mRNA, which may be regulated by SARS-CoV-2 to create a favorable environment for viral invasion.76

ACE2

ACE2 is the main receptor for SARS-CoV-2 entry, while its primary function in normal physiology is to convert angiotensin I and angiotensin II into angiotensin-(1-9) and angiotensin-(1-7), respectively.77 In the lower lung, type II alveolar cells is the major location where the ACE2 expresses, while the ACE2 expression is more pronounced in the upper bronchial epithelia and significantly elevated in the nasal epithelium, particularly within the ciliated cells.78 This distribution pattern aligns with the infection gradient of SARS-CoV-2, wherein nasal ciliated cells primarily serve as primary targets for viral infection during early stage.79 Severe COVID-19 patients possibly exhibit increased expression of ACE2 due to certain inflammatory cytokines such as interleukin-1β (IL-1β) and type I and II interferons (IFNs), and the result is the establishment of a positive-feedback loop, which facilitates viral replication.79,80

There are some ncRNAs serving antiviral role through inhibiting the ACE2. MiR-1246, which shares homology with ACE2 and targets its coding DNA sequence, has been identified as a negative modulator of ACE2 expression.81 Several studies have reported consistent upregulation of miR-1246 in the plasma of COVID-19 patients in comparison with healthy controls.43,51 Furthermore, miR-1246 expression level may increase with COVID-19 severity, as evidenced by consistent upregulation in severe patients compared to non-severe patients,31,43,50 indicating that with COVID-19 exacerbation, miR-1246 expression may gradually increase to prevent ACE2 expression and inhibit the viral invasion.82 In addition, the increased miR-200c-3p may directly target the 3’ untranslated region (UTR) of ACE2 and inhibit its expression in the epithelial cells.50,52,82 Similarly, other downregulated miRNAs namely miR-125-5P, miR-23b-5p and miR-769-5p can binds with 3’ UTR of ACE2 to block the virus entry and attachment.83

In line with the miRNAs changes, there were a lot of dysregulated DElncRNAs involved in SARS-CoV-2 invasion. The lncRNA GATA-binding protein 5 (GATA5), which is significantly elevated in severe cases, can also inhibit ACE2 gene expression to block the virus entry into host cells.54

TMPRSS2

The TMPRSS2 protein is classified as a type II transmembrane protein and exhibits serine protease activity. However, its precise physiological function remain poorly understood. Inhibition of TMPRSS2 through a small-molecule protease inhibitor can significantly prevent SARS-CoV-2 entry in both human lung epithelial cells and a transgenic mouse model of severe COVID-19, demonstrating the essential role of TMPRSS2 in SARS-CoV-2 invasion.84 In comparison with healthy controls, there was a marked increase in the expression of TMPRSS2 in lung epithelial cells from COVID-19 patients, particularly club and ciliated cells.85 Despite that the evidence about the relationship between host ncRNAs and TMPRSS2 after SASR-CoV-2 infection is still limited, it has been mechanistically validated that miR-98 can directly bind the 3’ UTR of TMPRSS2 in human endothelial cells including human lung microvascular endothelial cells and human umbilical vein endothelial cells, and subsequently can block the virus entry.86

Impact on SARS-CoV-2 replication

The overall life circle of SARS-CoV-2 includes not only the viral entry and endocytosis, but also the viral replication. After entry into the host cells, the virus produces multiple copies to spread inside the host body, following by the translation of the viral proteins or polypeptides. The SARS-CoV-2 genome harbors multiple open-reading frames (ORFs), encoding 16 nonstructural proteins (nsp 1–16) and necessitating the involvement of numerous proteins to sustain its replication cycle.87 Similar as the mRNAs, the viral genome also includes a 5’ cap structure along with a 3’ poly (A). Of these, the 5’ cap structure contains the sequence and UTR with stem-loop structures for RNA replication and translation. The 3’ UTR also embraces the structures required for viral RNA replication. In addition, the genome structure, 5’-UTR-replicase-S-E-M-N-3’ UTR-poly (A) tail, can create a suitable environment for virus replication and transcription.

The host ncRNAs have been highlighted in modulating the replication of SARS-CoV-2, possibly through directly targeting the viral genome or through virus-mediated alteration in the host transcriptome. Plasma miRNA profiling showed that the host miR-148a-3p can target virus genome, binding to the ORF1a, E, S and M genes and affecting virus entry and replication.88 Several downregulated miRNAs, including miR-497-5p, miR-21-3p and miR-195-5p, can target the coding strand of SARS-CoV-2, and lately inhibit its replication.89,90 In addition, some regulatory networks are controlled by the circRNA/lncRNA-miRNA-mRNA regulatory axis in the infected cells. Relevant research has reorganized a quintuple regulatory network including one miRNA (miR-124-3p), two circRNAs (ppp1r10 and C330019G07Rik) one lncRNA (Gm26917) and one hub gene Ddx58 in SARS-CoV cells. Ppp1r10 and C330019G07Rik can act as sponges for miR-124-3p to suppress Ddx58 degradation, resulting in the reduction of SARS-CoV-2 replication.63

Impact on immune response to SARS-CoV-2

Uncontrolled viral replication may trigger multiple immunopathologic conditions in host cells. As a result, SARS-CoV-2 can effectively inhibit or delay the induction or function of type I and III IFNs by infected cells, thereby circumventing or postponing the onset of intracellular innate immune responses and contributing to immunopathology.91–93 This temporal delay in innate immune response is sufficient to cause asymptomatic infection or clinically mild disease, as T cells and antibody responses can develop and control the infection.94,95 However, if there is a prolonged delay in priming the adaptive immune response due to impaired innate immunity, SARS-CoV-2 could undergo extensive replication in the upper respiratory tract and lungs. Consequently, innate immunity takes over adaptive immunity by amplifying its response to control the virus but leads to elevated levels of innate cytokine/chemokine molecules, triggering a phenomenon known as “cytokine storm”, along with dysregulated innate and adaptive immune cells observed in severe and critical disease.95,96 During this process, certain inflammasomes such as Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome would be activated, inducing release of pro-inflammatory factors and cell death.97

Host ncRNAs play a crucial function in regulating the innate and adaptive immune response.98–100 Although miRNA, lncRNA, and circRNA have distinct mechanisms of action, their roles in the host immune response to viral infection can be summarized as follows: (1) modulation of the IFN signaling pathway and inflammatory factors; (2) regulation of immune cell development and function, such as B- and T cells. In the case of SARS-CoV-2 infection, what is noteworthy is that the virus can also manipulate host ncRNAs for its own replication and infection by acting as a sponge or magnet to absorb or hijack ncRNAs involved in the immune system.101

The IFN pathway

The deficiency of IFN immunity in the respiratory tract may result in the SARS-CoV-2 spread, causing pulmonary and systemic inflammation. Some host ncRNAs play critical roles in modulating the IFN pathway.

Let-7b-5p can target the phosphodiesterase 12 (PDE12) which seems to regulate the IFN response. Enhanced resistance to virus infection was found through inhibition of the PDE12, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus.102 However, with the aggravation of the COVID-19, let-7b-5p showed downregulation in severe COVID-19 cases,48–50 in line with the abnormal type I IFN response in several and critical patients, featured with the absence of both IFN-β and IFN-α production and activity,103 suggesting a role of let-7b-5p in the impaired IFN deficiency and reduced resistance to SARS-CoV-2 via modulating the PDE12.

There is a significant correlation between the differential expression of lncRNAs with protein-coding genes associated with the immune system. The lncRNA LINC02384 can regulate IFN-γ expression to induce antiviral response and innate immune response.104 In addition, analysis of common miRNAs, circRNAs and mRNAs datasets revealed that hsa_circ_0080135 had multiple binding sites for 86 miRNAs, which were related to 15 mRNAs involved in cytokine storm including IL-1β, IL-7, IL-10, IL-12B, IL-13, IL-17A, IL-33, IFN-γ, C-C motif chemokine 2 (CCL2), C–X-C motif chemokine 6 (CXCL6), CXCL8, CXCL10, fibroblast growth factor (FGF2), FGF14 and macrophage inflammatory protein. On the other side, hsa_circ_0080135 also acted as ceRNA of miR-769-3p targeting IL-12B, IFN-γ, CXCL6 and CXCL8 to regulate cytokine storm.105 By targeting ncRNAs, plenty of dysregulated cytokines during SARS-CoV-2 infection were involved in the circRNA/lncRNA-miRNA-mRNA axis.

Inflammatory cascades

After SARS-CoV-2 infection, both pro-inflammatory and anti-inflammatory cytokines exhibit a dramatic elevation, and their expression and function can be mediated by host ncRNAs.106 One example is miR-106b-5p, which is a modulator of the lysine acetyltransferase 2B (KAT2B).107 Either pharmacological inhibition or knockdown of KAT2B resulted in decreased level of IL-10 in normal colonic epithelial cell line.108 In COVID-19 cases, KAT2B showed upregulation, while miR-106b-5p was downregulated, suggesting a possible routine that the decreased miR-106b-5p induced by SARS-CoV-2 results in high expression of KAT2B and promotes the IL-10 level.50,52,107

LncRNAs, particularly nuclear paraspeckle assembly transcript 1 (NEAT1) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), have been shown to play critical roles in the expression of pro-inflammatory cytokines. In patients infected with higher viral loads of SARS-CoV-2, a greater proportion of upregulated transcripts were represented by lncRNAs, which functionally correlated with lymphocyte activation and cytokine signaling.109 NEAT1 shows high correlation with the cytokines110 and can serve as an immunoregulator on promoting the monocyte-macrophage differentiation.111 Further, knockdown of NEAT1 in the human monocyte-macrophage cells inhibited the apoptosis and reduced the expression of cyclooxygenase-2 (COX-2) and several pro-inflammatory cytokines, such as the IL-6 and tumor necrosis factor α (TNF-α), possibly through targeting miR-342-3p.112 In the COVID-19 cases, NEAT1 was upregulated,36,50,113 and consistently, miR-342-3p was downregulated,43 indicating that overexpressed NEAT1 may facilitate the pro-inflammatory process through repressing miR-342-3p after SARS-CoV-2 infection.

CircRNAs also acts a pivotal function in the formation of pro-inflammatory cytokines. Compared with the healthy controls, hsa_circ_0000479 exhibited increased level in COVID-19 patients, along with the upregulation of retinoic acid-inducible gene I (RIG-I) and IL-6, and downregulation of miR-149-5p.114 Overexpressed hsa_circ_0000479 can indirectly stimulate the RIG-I through binding to miR-149-5p, and the activated RIG-I would trigger the expression of IL-6.115,116 Therefore, a hsa_circ_0000479 composed circRNA-miRNA-mRNA regulatory axis may serves a critical function in mediating the pro-inflammatory cytokines expression after SARS-CoV-2 infection.

T cells development and function

After almost all SARS-CoV-2 infections, T-cell responses can be detected. In a study recruiting 116 hospitalized COVID-19 patients with varying severity, mass cytometry of whole blood found decreased overall T cells and increased activated and cytotoxic CD8+ T cells in more severe cases, indicating a dysregulation of T-cell response in severe COVID-19 disease.117 The two upregulated DElncRNAs HIF1alpha-antisense RNA 1 (HIF1A-AS-1) and retinoid acid receptor-related orphan receptor alpha-antisense 7 (RORA-AS-7) were enriched in differentiation of T-helper cells, which can regulate T-cell differentiation, while the detailed underpinnings merit more investigations.42

Impact on multiorgan deficits and long COVID

COVID-19 is recognized as a respiratory disease that causes significant pulmonary damage, but with disease progression, numerous extrapulmonary symptoms have been reported in patients, affecting various systems such as cardiovascular, neurological and endocrinological. There are various hypotheses about the pathogenesis of multiorgan failure in COVID-19, such as dysregulated immune response, viral toxicity, and throboinflammation.68,118,119 Of these, direct viral invasion-induced toxicity may be unique, due to organotropism of SARS-CoV-2 toward the respiratory tract, neurologic, myocardial, pharyngeal and gastrointestinal tissues along with wide expression of ACE2 and TMPRSS2 in the host body.120,121 COVID-19 progression is not limited to moderate or severe cases, as recent studies have demonstrated the persistence of a range of symptoms following acute infection, commonly referred to long COVID.122 Some hypotheses about the long COVID pathogenesis have been proposed, such as impaired autoimmunity, viral remnants, dysregulated dysbiosis, and tissue damage.7 However, the detailed mechanism that underlies long COVID remains unclear.

In light of the organ-specific functions exhibited by host ncRNAs, we elucidate their respective roles across different anatomical systems below, and the following findings suggest that the inflammatory signaling and tissue development both represent the predominant targets for host ncRNAs in regulating the progression of organ failures within the context of COVID-19.

Respiratory system

For COVID-19 cases, up to 20% will develop to a severe form, featured with the occurrence of COVID-19-associated ARDS, severe pneumonia, and pulmonary fibrosis.123 Furthermore, several investigations have reported persistent lung injury even after clearance of SARS-CoV-2. A meta-analysis examining chest computed tomography (CT) findings about 12 months post COVID-19 revealed that around 33% of patients still exhibited residual lung abnormalities on CT scans. These findings suggest that SARS-CoV-2 infection possibly leads to prolonged lung injury.124 Current perspectives on the pathogenesis of lung injury in COVID-19 primarily focus on direct viral damage and host immune response.125

As previously mentioned, dysregulated immune systems can trigger a cytokine storm that can damage alveolar structures, allowing the virus to invade vascular endothelial cells from the blood-air barrier. With the disease advances, endothelial dysfunction results in increased rigidity and susceptibility of pulmonary vessels., ultimately resulting in thrombosis and microvessels blockage in alveolar capillaries, potentially causing hypoxemia or pulmonary hypertension.123 The circulating miR-486-5p, which is decreased in COVID-19, can targets the OUT domain-containing protein 7B (OTUD7B) genes to regulate antiviral response and promotes acute lung injury.88 Several lncRNAs including MALAT-1 and structural maintenance of chromosomes 2-antisense 1 (SMC2-AS1), which separately regulates the IL-8, calpain-1 catalytic subunit 1 (CAPN1), Wnt, and TGF-β signaling pathway, are also essential to regulates lung repair and regeneration.50,126

Cardiac system

More than 7% COVID-19 patients experience myocardial injury from the infection, and over 25% of hospitalized cases showed an elevated level of troponin (a marker of cardiac dysfunction).127–129 Despite the mechanism underlying the cardiac injury after SARS-CoV-2 infection remains uncertain, direct viral damage received much attention. Many studies have showed that SARS-CoV-2 RNA can be observed in the heart from some COVID-19 cases.120,130 In addition, the cardiac myocyte apoptosis induced by cytokine storm and hypoxia-induced excessive intracellular calcium may also account for the cardiac injury in the context of COVID-19.131

The miR-208a and miR-499, two heart-muscle specific miRNAs, showed significant upregulation in the COVID-19 patients compared to the influenza-ARDS patients, possibly indicating chronic myocardial damage after SARS-CoV-2 infection.46 Otherwise, the miRNA miR-133a, which can regulate neutrophil counts and degranulation, plays important roles in inflammation-induced myocyte damage.49

Central nervous system

SARS-CoV-2 has been identified to significantly affect the central nervous system (CNS). Reports indicate that ~30% of hospitalized COVID-19 cases, 45% of severe cases, and 85% of patients with ARDS exhibit neurological symptoms.132,133

Current hypotheses aiming at the influence of SARS-CoV-2 on the CNS primarily focus on neuroinflammation and tissue damage, both of which involve host ncRNAs.134 Several ncRNAs show potential for modulating the immune process of neural cells. As we screened, an important lncRNA NEAT1, its elevation can regulate the inflammation of neurons and involve in the susceptibility to COVID-19 infection.135,136 Upregulated NEAT1 was also reported in patients with ischemic stroke, and knockdown of NEAT1 can alleviate the apoptosis and improve neuronal viability.137 This result suggests a possible role of NEAT1 in the pathogenesis of stroke in COVID-19 cases. Moreover, some miRNAs, such as let-7c-5p, were reported to emerge as neuroprotective factors to inhibit microglia activation.138 Overexpression of let-7c-5p can reduce the infarction volume and improve the neurologic deficits. The SARS-CoV-2 has been observed in human brain vessels and can infect and damage neurons, indicating that the nervous system is vulnerable to attack by SARS-CoV-2.139–142

Psychiatric and neurological symptoms have been frequently reported in COVID-19 survivors for up to 12 months following infection, with the estimated prevalence of 19.7% and 18.7%, respectively.9 Sleep disturbances, depression, insomnia, anxiety symptoms, and cognitive impairment are prevalent in these individuals, placing a significant burden on their well-being.143 Besides, long COVID cases have reported experiencing “brain fog,” which is characterized by the feeling of being mentally slow or fuzzy.144,145 One potential mechanism by which ncRNAs may contribute to the development of neuropsychiatric sequelae is through modulation of aberrant neurotransmitter levels resulting from hyperinflammation. In individuals who recovered from COVID-19, miR-15a-5p was upregulated compared with that in healthy control, along with decreased serum soluble programmed cell death protein-1 (PD-1, a direct target of miR-15a-5p) and increased cytokines, including IL-1β, IL-1RA, and IL-8.146 The abnormal PD-1 signal may result in dysregulated T-cell functions, and inhibition of PD-1 can reduce the availability of tryptophan and tyrosine in the mice brain and repress the synthesis of serotonin and dopamine, leading to enhanced anxiety-like behaviors and fear response.147 These data suggest a function of the abnormal miR-15a-5p/PD-1 axis in the depression, anxiety or post-traumatic stress disorder symptoms in long COVID cases. Moreover, the function of miR-15a-5p in neuropsychiatric sequela of COVID-19 has more possibilities. Ataxin-7-like protein 3B (ATXN7L3B), a downstream target of miR-15a-5p, showed an involvement in human neurodevelopmental delay and ataxia,148 which possibly have a more dramatic effect on brain development in children who had been infected with SARS-CoV-2.

Peripheral nervous system

SARS-CoV-2 also induces a plethora of peripheral nervous system diseases both acutely and chronically. The common peripheral manifestations of COVID-19 include muscle pain, injury, fatigue and weakness. In COVID-19, skeletal muscle injury present in 19.3% of individuals who are severely ill and 4.8% of individuals in non-severe group.133 Fatigue and weakness have been commonly reported in individuals who recovered from COVID-19. Studies have showed that 32% of individuals continued to experience fatigue for 12 or more weeks after their initial COVID-19 diagnosis.149 Fatigue is characterized by an overwhelming feeling of tiredness or lack of energy, while weakness refers to a decrease in muscle strength.150 The skeletal muscles and other cells in muscles, including leukocytes, fibroblasts and endothelial cells, also express ACE2 receptors. Therefore, it suggests that skeletal muscles are susceptible to virus invasion and immune-mediated myopathies.151 The common gene interaction networks were shown between the long COVID and myalgic encephalomyelitis/chronic fatigue syndrome, involving 9 common genes and 102 miRNAs.152 In addition, a correlation was found between the downregulated let-7b-5p in convalescent individuals after SARS-CoV-2 infection and the master regulatory gene paired box protein 3 (PAX3).42 PAX3 can mediate muscle function and protect muscle satellite cells from environmental stress.153,154 Further, it has been reported that upregulation of Pax3 in the myogenic differentiation antigen (MyoD−/−) myoblasts was accompanied with activated transcription of antiapoptotic factors B-cell lymphoma/leukemia-2 (Bcl-2) and Bcl-2-like protein-1 (Bcl-xL),155 while persistent expression of Pax3 would inhibit myogenic differentiation, indicating that approximate Pax3 degradation is critical for the progression of the myogenic program.156

NcRNAs as biomarkers for COVID-19

Given the involvement of host ncRNAs in diverse processes including viral invasion and replication, immune response, multiorgan damage, and the occurrence of long COVID resulted from SARS-CoV-2 virus, distinct ncRNAs have emerged as potential biomarkers for each of these processes. Currently, ncRNAs have been utilized as promising biomarkers for kinds of diseases, mostly for multiple types of cancer,10,11 while the diagnostic utility of host ncRNAs may be limited in the context of COVID-19. Three diagnostic tests are commonly employed for COVID-19, encompassing molecular testing using nasopharyngeal or nasal swabs to detect viral RNA, antigen testing to identify viral proteins, and serology testing to detect host antibodies in response to infection, and the first two methods can be utilized for diagnosing acute infections.157

Host ncRNAs may provide advantages in closely monitoring and evaluating the development of COVID-19 disease. According to WHO,158 severe COVID-19 patients are defined by any of: (1) oxygen saturation less than 90% on room air; (2) severe pneumonia; (3) signs of severe respiratory distress. The critical COVID-19 patients are defined by the criteria for ARDS, sepsis, septic shock, or other conditions that would normally require the provision of life-sustaining therapies such as mechanical ventilation or vasopressor therapy. Meanwhile, the WHO has also provided corresponding management and treatment recommendations for patients with different severity levels. During these processes, relying solely on clinical symptoms for disease progression assessment may lead to treatment delays, as molecular alterations in the body might have already occurred prior to symptom manifestation. Therefore, utilizing ncRNAs to assist the disease management can facilitate the convenience in monitoring the progression of COVID-19 and offer significant advantages in delivering timely treatment recommendations and measures. Additionally, compared to other molecular biomarkers, ncRNA possesses some features that make it a valuable tool in clinical use, including its tissue-specificity, cell-specificity, developmental stage-specificity, and stability.159 In the following section, we present a comprehensive overview of the current research on potential biomarker ncRNAs for COVID-19 diagnosis, stratification, prognostic evaluation, and treatment response (Fig. 3a).Fig. 3 Summary of the clinical applications of ncRNAs-based biomarkers and therapeutic strategies against COVID-19. a Some host ncRNAs can be used as biomarkers in various clinical scenarios after SARS-CoV-2 infection, including auxiliary diagnosis of the COVID-19 (e.g., miR-155, SNHG16, hsa_circ_0000479), differentiation of the disease severity (e.g., miR-155, miR-148a-3p, miR-486-5p, miR-451a, miR-369-3p, GAS5, lncRNA RP11-773H22.4), distinguishing the survivors compared to non-survivors (e.g., a signature consisting of miR-22-3p, miR-3180-3p, let-7f-1-3p, let-7g-5p, miR-1255a, miR-140-3p, miR-20a-5p, miR-363-5p, miR-4510, and miR-6130), distinguishing the post-acute patients compared to healthy controls/acute patients (e.g., miR-146a-3p, miR-29a-3p, let-7b-3p, THRIL, MALAT-1), and indicating the treatment response (e.g., miR-31-3p, miR-29a-3p, miR-126-3p, miR-146a-5p). b The current therapeutics for COVID-19 patients, including (i) antiviral drugs, (ii) monoclonal antibody, (iii) convalescent plasma therapy and (iv) new drug development (ncRNAs-based strategy, e.g., circRNARBD-Delta). c Potential therapeutical strategies based on ncRNAs. Restoration of miRNA level: the miRNA mimics and agomirs can be synthesized and delivered into the cells to increase the level of a target miRNA. Targeting ncRNAs at the DNA level: using CRISPRi and CRISPRa tools to transcriptionally inhibit or activate target ncRNA expression. Targeting ncRNAs at the RNA level: (i) The siRNA targets at ncRNAs in the RISC complex and initiate degradation of ncRNAs; (ii) ASOs can bind the target ncRNAs and induce its degradation by recruitment of Ribonuclease (RNaseH1); (iii) CircRNAs emerge as the sponges of miRNAs to restrain their bio-accessibility to mRNA; (iv) CircRNAs directly bind the viral mRNA to inhibit their propagation

Diagnostic biomarkers for COVID-19

Some patients may persistently exhibit negative test results despite displaying clinical symptoms.157 Considering that the expression profiles of host miRNAs or lncRNAs are highly sensitive, with changes observed even between the acute phase (within 3 days) and later stages (approximately 7 days), and thus, host ncRNAs could serve as a valuable tool for confirming clinical diagnoses.41,44,55 For instance, the miR-155 molecule has been extensively recognized as a pivotal regulator of immune cells throughout evolution and serves a crucial role in the development of progressive inflammatory diseases.41 It exhibited a remarkably high area under the curve (AUC) value of 0.99 for COVID-19 diagnosis.160 Whether this differential expression of miR-155 is induced by SARS-CoV-2 infection or just due to the inflammatory response merits more investigations. However, an investigation reported that it was also upregulated of the miR-155 in the COVID-19 individuals compared to influenza-ARDS cases, showing a strong discrimination with an AUC of 1.00.46 More validations are worthy to identify whether miR-155 serves a specific function in the COVID-19 pathogenesis.

Several lncRNAs and circRNAs have also demonstrated promising outcomes. Among them, small nucleolar RNA host gene 16 (SNHG16) can activate the TGF pathway and participate in inflammatory cascades; its expression was found to be downregulated in COVID-19 cases compared to controls. Furthermore, SNHG16 holds potential as a biomarker for distinguishing COVID-19 cases from healthy controls with an AUC of 0.67, sensitivity of 0.70, and specificity of 0.59.161 CircRNA has_circ_0000479 also showed upregulation in the COVID-19 patients, with a negative correlation with IL-6 expression.114

Stratification biomarkers for COVID-19

Most individuals infected with COVID-19 typically experience mild (40%) or moderate (40%) manifestations of the disease. Approximately 15% progress to a severe stage necessitating oxygen support, while 5% develop critical illness characterized by complications likely respiratory failure, ARDS, sepsis and septic shock, thromboembolism, and/or multiorgan failure.162 Distinguishing between non-severe and severe COVID-19 patients is reliant on certain diagnostic examinations, including respiratory rate and chest CT. The availability of more accessible biomarkers for monitoring disease severity could facilitate prompt and appropriate treatment for patients. A selection of potential host miRNAs and lncRNAs were identified for discriminating COVID-19 severity (Table 2).Table 2 Host miRNAs and lncRNAs with potential roles in discriminating COVID-19 and predicting clinical outcomes

Application	Host ncRNAs	Biological functions related with COVID-19 pathogenesis	Source	Expression	Sample size	AUC	Sensitivity	specificity	P value	Ref.	
Discriminating COVID-19 patients with different severities	
 Distinguishes between severe and moderate COVID-19 patients	miR-155	Regulating inflammatory-related proteins, immunomodulatory proteins, and tumor-supressor proteins	Plasma	Upregulation in severe cases	150	0.75	0.76	0.76	NA	160	
	miR-200	Downregulating ACE2 expression, increasing angiotensin II level	Serum	Upregulation in severe cases	200	0.66	0.65	0.63	<0.0001	167	
	GAS5	Regulating the miR-200/ACE2 axis involved in the occurrence of ARDS	Serum	Downregulation in severe cases	200	0.74	0.74	0.71	<0.0001	167	
 Distinguishes between severe and mild COVID-19 patients	lncRNA RP11-773H22.4	Regulating inflammation	Serum	Upregulation in severe cases	200	0.78	0.78	0.71	0.05	32	
 Distinguishes between ICU and ward COVID-19 patients	A signature consisting of miR-148a-3p, miR-486-5p, and miR-451a	miR-148a-3p targeting in the ORF1a, E, S, and M genes in the SARS-CoV viral genome; miR-486-5p promoting acute lung injury by inducing inflammation; miR-451a regulating cytokine and chemokine synthesis	Plasma	miR-148a-3p upregulation in ICU cases; miR-486-5p and miR-451a downregulation in ICU cases	79	0.89	NA	NA	NA	88	
 Distinguishing between COVID-19 patients with ARDS requiring MV and patients without MV	miR-369-3p	A dual role in both immune system regulation and viral performance	Serum	Downregulation in COVID-19 patients with ARDS requiring MV	20	0.72	NA	NA	0.05	165	
Predicting COVID-19 clinical outcomes	
 Predicting COVID-19-related death at 90 days	A signature including miR-22-3p, miR-3180-3p, let-7f-1-3p, let-7g-5p, miR-1255a, miR-140-3p, miR-20a-5p, miR-363-5p, miR-4510, and miR-6130	let-7g-5p, miR-363-5p, and miR-4510 targeting the SARS-CoV-2 genome; miR-140-3p targeting the serine protease TMRSS2 which process the viral invasion; miR-20a-5p targeting several proteins which may mediate SARS-CoV-2 induced cell death	Plasma	NA	96	0.97	0.92	0.93	NA	43	
 Differentiating ICU non-survivors from survivors	A signature including miR-192-5p and miR-323a-3p	miR-192-5p regulating cytokine and chemokine synthesis; miR-323a-3p inhibiting replication of the viral infection	Plasma	Downregulation in ICU non-survivors	36	0.80	NA	NA	NA	88	
 Differentiating COVID-19 non-survivors from patients who died due to other causes	miR-26a-5p	Involving in endothelial dysfunction and viral infection	Lung biopsies	Downregulation in COVID-19 cases	19	0.83	NA	NA	0.06	40	
	miR-29b-3p	Involving in immune and adaptive response	Lung biopsies	Downregulation in COVID-19 cases	19	0.81	NA	NA	0.05	40	
Discriminating post-acute COVID-19 patient	
 Distinguishing post-acute COVID-19 patients from healthy control	miR-146a-3p	Positively correlated with dry cough, fever, and decreased smell	PBMCs	Upregulation in post-acute COVID-19 cases	33	0.98	NA	NA	<0.0001	45	
	miR-29a-3p	Positively correlated with dry cough	PBMCs	Upregulation in post-acute COVID-19 cases	33	1	NA	NA	<0.0001	45	
	let-7b-3p	Positively correlated with dry cough	PBMCs	Upregulation in post-acute COVID-19 cases	33	0.93	NA	NA	<0.0001	45	
	miR-155-5p	Regulating inflammation and antiviral cellular defense	PBMCs	Upregulation in post-acute COVID-19 cases	40	0.83	NA	NA	<0.0001	41	
 Distinguishing acute COVID-19 patients from post-acute patients	miR-146a-3p	Positively correlated with dry cough, fever, and decreased smell	PBMCs	Upregulation in post-acute COVID-19 cases	18	0.80	NA	NA	0.001	45	
	miR-29a-3p	Positively correlated with dry cough	PBMCs	Upregulation in post-acute COVID-19 cases	18	0.82	NA	NA	0.001	45	
	THRIL	Controlling the expression of TNF-α signaling which regulates inflammation and immune response	PBMCs	Downregulation in post-acute COVID-19 cases	20	0.75	NA	NA	0.005	41	
	MALAT-1	Controlling cytokine secretion in macrophages under inflammatory circumstances and promoting inflammatory activity by interacting with the NF-κB pathway	PBMCs	Downregulation in post-acute COVID-19 cases	20	0.72	NA	NA	0.021	41	
ARDS associated acute respiratory distress syndrome, GAS5 arrest-specific transcript 5, MALAT-1 metastasis-associated lung adenocarcinoma transcript 1, ORF open-reading frame, PB peripheral blood, PBMCs peripheral blood mononuclear cells, THRIL TNF and HNRNPL-related immunoregulatory long non-coding RNA

MiR-155 plays a pivotal function in the regulation of inflammatory-related proteins and immunomodulatory proteins, exhibiting distinct expression patterns between either COVID-19 patients and healthy controls or severe and moderate cases.160 Haroun et al. identified an upregulation of plasma miR-155 in severe COVID-19 cases using RT-qPCR. Furthermore, they consistently observed a significant positive correlation between its expression level and clinical parameters likely chest CT findings, C-reactive protein (CRP), and ferritin levels. The AUC for miR-155 in distinguishing severe from moderate cases was 0.75, with a sensitivity and specificity of 0.76 each.160 Considering the above promising diagnostic implications,45 miR-155 holds more potential as an indicator for long-term monitoring of COVID-19 progression.

Certain miRNAs, including miR-148a-3p, miR-486-5p, and miR-451a, exhibit potential for distinguishing between COVID-19 patients in the intensive care unit (ICU) and those in general wards. As we have mentioned in the above section, miR-148a-3p can target various genes within the SARS-CoV2 genome (ORF1a, E, S, and M), and the other two miRNAs have been reported with dysregulated B and T lymphocytes, chronic inflammatory response, and acute lung injury.163,164 De Gonzalo et al. observed an upregulation of miR-148a-3p and downregulation of both miR-486-5p and miR-451a among ICU cases’ serum samples. The AUC value of a signature consisting of these three miRNAs for differentiating between ICU patients versus ward patients was 0.89, which was higher than other molecular biomarkers, such as leukocyte counts (AUC = 0.74), D-dimer (AUC = 0.87), or CRP (AUC = 0.72), indicating a value of miRNAs as biomarker for evaluating the COVID-19 development.

In addition to classifying disease severity, certain ncRNAs have the potential to predict adverse outcomes characterized by a rapid onset, as many miRNAs and lncRNAs showed differential expression in COVID-19 patients between the acute period (within 3 days) and later phage (7 days).44,55 Moreover, by comparing COVID-19 patients with ARDS requiring mechanical ventilation to those without mechanical ventilation, a significant downregulation of miR-369-3p was identified in the serum of patients needing mechanical ventilation. Furthermore, its AUC for discriminating between patients with and without mechanical ventilation was calculated as 0.72.165 Numerous studies have reported that miR-369-3p plays a dual role in both immune system regulation and viral performance; its downregulation can promote the production of inflammatory factors and it possesses a target site within the SARS-CoV-2 genome, indicating that the dysregulation of miR-369-3p following the onset of disease may facilitate and expedite the development of ARDS after SARS-CoV-2 infection.165

LncRNAs can also be utilized biomarkers for distinguishing the disease severity. For instance, lncRNA growth arrest-specific transcript 5 (GAS5) participated in promoting ACE2 expression by inhibiting miR-200.166 Accordingly, a contrasting expression pattern of GAS5 and miR-200 was observed in the serum samples from 88 severe COVID-19 cases compared to 112 moderate cases, with a downregulation of GAS5 and an upregulation of miR-200.167 Notably, GAS5 exhibited superior discriminatory performance between severe and moderate patients, as evidenced by an AUC of 0.74 (sensitivity=0.74, specificity=0.71), while miR-200 demonstrated an AUC of 0.66 (sensitivity=0.65, specificity=0.63). LncRNA RP11-773H22.4 also showed potential for differentiating severe and mild COVID-19 patients; its serum expression was increased in the severe patients compared to mild ones, which could cause downregulated miR-4257 and subsequently upregulated IL-11 receptor subunit alpha (IL-11RA) mRNA thereby promoting inflammation.32 The AUC for lncRNA RP11-773H22.4 in this cohort was 0.78, with a sensitivity of 0.78 and specificity of 0.71. Additionally, multivariate analysis revealed that lncRNA RP11-773H22.4 was an independent factor besides serum ferritin level and CT findings, demonstrating its promising role as a predictor for COVID-19 severity.

Prognostic biomarkers for COVID-19

Survivors vs. non-survivors

As the disease progresses, some patients may succumb to it. A systematic analysis of COVID-19-related mortality from 2020 to 2021 revealed a global all-age excess mortality rate of 120.3 deaths (113.1–129.3) per 100,000 population due to COVID-19.168 Therefore, it is imperative to investigate early markers for the COVID-19 clinical outcomes forecast, and certain miRNAs exhibit potential in this domain. Collecting the plasma sample from COVID-19 patients upon hospital admission or within the first few days after hospitalization but before treatment, 77 upregulated miRNAs and 60 downregulated miRNAs in severe cases were identified.43 Furthermore, a mortality predictive model consisting of ten miRNAs (miR-22-3p, miR-3180-3p, let-7f-1-3p, let-7g-5p, miR-1255a, miR-140-3p, miR-20a-5p, miR-363-5p, miR-4510, and miR-6130) was constructed and confirmed to have better predictive power than the basic model that only considered age and gender (AUC: 0.97 vs. 0.88), along with over 90% sensitivity and specificity. Similarly, miR-192-5p and miR-323a-3p showed downregulation in ICU COVID-19 non-survivors compared with the survivors, and a signature composed of them can be utilized for discriminating the non-survivors from survivors with an AUC of 0.8. Among the above host miRNAs, some of them (e.g., let-7g-tp, miR-363-5p, and miR-4510) can target the SARS-CoV-2 genome, and miR-323a-3p may play an inhibitory role in viral replication; miR-140-3p can target the serine protease TMPRSS2, showing a role in regulating the viral invasion; miR-20a-5p and miR-192-5p can participant in the host response, such as cell death and cytokine synthesis.43,88 The dysregulated expression of these host miRNAs indicates a distinction in viral invasion and replication as well as subsequent host response between COVID-19 non-survivors and survivors, potentially manifesting earlier than clinical symptoms. Therefore, these miRNAs may serve as both prognostic biomarkers for mortality risk prediction and therapeutic targets for mitigating COVID-19 progression.

Post-acute patients vs. healthy control/acute patients

Following the acute phase, a considerable number of patients may encounter persistent manifestations subsequent to their initial symptomatic SARS-CoV-2 infection, commonly named as long COVID. The host ncRNAs may be involved in this process, as evidenced either by the identification of numerous host DEmiRNAs and DElncRNAs during the recovery stage of COVID-19 or the possible functions in the persistent organ failures.42 In line with these findings, a study comparing host miRNAs in PBMCs between the post-acute phase COVID-19 patients (4–5 weeks after the acute phase) and the healthy controls revealed upregulation of three miRNAs (miR-146a-3p, miR-29a-3p, let-7b-3p) among post-acute cases.45 All three exhibited an AUC value above 0.9 for discriminating between post-acute COVID-19 cases and healthy controls. Furthermore, the expression levels of miR-146a-3p and miR-29a-3p were found to be higher in PBMCs during the post-acute stage compared to the acute phase, indicating a progressive increase in their expressions throughout COVID-19 development. Some findings indicate that miR-146a possibly exerts a protective effect on the virus by suppressing signal transducer and activator of transcription 1 (STAT1) protein, thereby impeding SARS-CoV-2 replication and evading antiviral response.169,170 Moreover, previous studies demonstrated that miR-146a-3p negatively regulated the Sirtuin-1/noncanonical nuclear factor-κB (NF-κB) axis to contribute to acute lung injury.45,171 This is consistent with that miR-146a has been shown to target 21 differentially expressed genes (DEGs) in lung tissues of COVID-19 patients.172 Accordingly, a positive correlation was observed between miR-146a-3p expression and manifestations such as fever, and coughing in COVID-19 cases. Consequently, stepwise upregulation of miR-146a-3p may play a role in persistent post-acute phase symptoms or even long COVID through various cascades, indicating its potential for closely monitoring COVID-19 development. A positive correlation was also observed between the expression of miR-29a-3p and dry cough in COVID-19 cases.45 However, further investigations are required to determine whether this miRNA exerts an antiviral or pro-viral function in SARS-CoV-2 pathogenesis, as some findings have shown downregulation of miR-29a-3p in the plasma of ARDS patients and administration of miR-29a-3p agomir can inhibit the expression of inflammatory factors in the lung.173

Certain lncRNAs, such as TNF-α and heterogeneous nuclear ribonucleoprotein L (THRIL) and MALAT-1, exhibited differential expression between post-acute and acute COVID-19 patients. THRIL can modulate TNF-α expression by interacting with heterogeneous nuclear ribonucleoprotein L, promoting inflammation and immune response.174 Similarly, MALAT-1 can regulate cytokine secretion and contribute to inflammatory activity through targeting the NF-κB pathway.175 The expressions of these lncRNAs in PBMCs were significantly decreased during the post-acute phase (6–7 weeks after the acute phase), with AUC values for discriminating the post-acute cases from acute cases of 0.75 for THRIL and 0.72 for MALAT-1, respectively. Further, a positive correlation was identified between dry cough and THRIL expression, while fever and skeletal pain showed a positive correlation with MALAT-1 expression, indicating possible involvement of host lncRNAs in persistent manifestations.41

Predictive biomarkers for COVID-19 treatment response

In addition to monitoring and predicting the development of COVID-19, certain host miRNAs exhibit specific expression patterns in response to COVID-19 treatment. Notably, hospitalized patients with varying disease severity demonstrated significant downregulation of miR-31-3p, miR-29a-3p, and miR-126-3p levels. However, in patients treated with remdesivir and favipiravir during hospitalization, the expression of these three miRNAs returned to baseline levels in treatment-responsive patients compared to non-responsive individuals.176 Considering that miR-29a-3p also exhibited increased expression during the recovery stage compared to the acute phase, it can be speculated that this particular miRNA possibly acts as an marker of COVID-19 improvement and possibly play a pro-viral function. Another study analyzing serum samples from COVID-19 cases with multifocal interstitial pneumonia who received a single-dose intravenous infusion of tocilizumab—an anti-IL-6 receptor drug—revealed a marked increase in serum levels of miR-146a-5p among treatment-responsive patients. This finding is in line with its downregulation observed in COVID-19 patients in comparison with the healthy.50,177 These host miRNAs exhibit potential as predictive markers for personalized treatment response, thereby aiding in enhancing the efficacy of COVID-19 therapies. Further investigations are worthy to explore whether there exist host lncRNAs or circRNAs with analogous functionalities.

Demographic factors influencing the expression of host ncRNAs

The severity and mortality of COVID-19, including long COVID, are influenced by various factors such as age, sex, and pre-existing comorbidities. A number of studies have shown that elderly individuals or males are frequently associated with worse COVID-19 prognosis.178–180 In turn, these demographic variables may also impact the host ncRNAs expression. Comparing COVID-19 patients in different conditions can aids in identifying DEncRNAs as potential biomarkers for targeted populations. However, the comprehensive impact of these factors on ncRNAs in COVID-19 patients remains inadequately documented. Current research has been limited to detecting changes in a specific type of miRNA using PCR methodology, and whether these differences extend to lncRNAs and circRNAs remains largely unexplored.

Some miRNAs exhibited an association with age in the context of COVID-19. The miR-10b (a miRNA regulating the cytokines) showed a negative correlation with the age of COVID-19 cases, along with a downregulation in COVID-19 patients compared with age-matched healthy controls, indicating that a greater decrease of miR-10b per age may be associated with the higher inflammation in the older COVID-19 patients.30 In addition, is there any differential expression of miRNA in COVID-19 patients across different age groups? Evidence from high-throughput methods remains limited, but a study utilizing RT-qPCR demonstrated that miR-200c-3p was upregulated in saliva samples of COVID-19 cases over the age of 42 compared to those under 42 years old.181 Combined with the finding that miR-200c-3p showed higher expression in severe COVID-19 cases vs. healthy control, it suggests that some miRNAs in older patients may contribute to increased inflammation and cytokine storm, thereby exacerbating disease severity and mortality.52,181

Sex and comorbidities can also affect the expression of host miRNAs in the context of COVID-19. Comparing with female COVID-19 cases, miR-10b was downregulated in the male ones who more possibly experienced frequent infection, poor clinical outcomes, and higher mortality.179,182 Besides, pre-existing comorbidities may modulate the severity of COVID-19 via miRNAs, due to a preliminary result that the expression of miR-200c-3p was independently associated with COVID-19 cases with hypertension.181

The overall findings of these investigations suggest a correlation between changes in the expression of certain miRNAs and age, gender or comorbidity in COVID-19 patients, potentially shedding light on the more severe symptoms observed in older or male patients and those with comorbidities. However, it is important to note that further investigations with larger sample sizes and advanced sequencing or microarray techniques are needed to determine whether these results specifically stem from the SARS-CoV-2 infection and whether can generalize to lncRNAs and circRNA.

NcRNAs-based therapeutics for COVID-19

The emergence of specific therapies designed to modulate ncRNAs has opened up new possibilities for their use as therapeutic targets. Such strategies typically involve interventions that target the transcriptional activation or inhibition of ncRNA expression loci at either the RNA or DNA level. Examples of these interventions include the use of mimics, agomirs, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) tools, antisense oligonucleotides (ASOs), and RNAi knockdown.11 The advancements made in gene editing techniques have resulted in an increase in the number of preclinical and clinical investigations which have explored the potential use of ncRNA candidates for treating a variety of diseases, such as liver cancer,183 viral hepatitis C,184 cardiovascular disease,185 and Alzheimer’s disease.186 Given this promising trend and important functions in the pathogenesis of COVID-19, ncRNAs may also represent a viable therapeutic approach for treating COVID-19, including cases of long COVID.

Potential therapeutic targets of ncRNAs

One potential routine is the intervention of virus infection. Specifically, miR-150-5p shows great therapeutic values for the treatment of such infection. Increasing the expression level of miR-150-5p through the utilization of mimics has been recognized to attenuate SARS-CoV-2 infection in vitro, while inhibition of miR-150-5p can reverse this effect.187 Other ncRNAs, including miR-106-5p, let-7b-5p, and NEAT1, have also emerged as potential therapeutic targets due to their contributions to immune response and cellular development.

Repairment of immune response is the paramount treatment for COVID-19. NcRNAs-based therapeutics that target specific immune factors nucleotide sequences may mitigate inflammatory and cytokine storms, and ameliorate the immune response to SARS-CoV-2 infection.

NcRNAs may also act as targets for treating the neuropsychiatric symptoms or sequela following SARS-CoV-2 infection, with miRNAs such as miR-15a-5p and let-7 family playing essential roles as regulators of brain development in association with ataxia-associated genes such as ATXN1, ATXN1L, and ATXN7L3B.

Promising therapies modulating the host ncRNAs

Thus far, a variety of therapeutics have been employed in clinical settings for treating COVID-19, which can be broadly categorized into three categories (Fig. 3b): drug repurposing, monoclonal antibody and convalescent plasma therapy. Several drug/vaccines have been successfully developed and used in COVID-19 patients, such as antiviral drug (remdesivir), hydroxychloroquine, combination of two anti-human immunodeficiency virus (HIV) drugs (lopinavir and ritonavir), glucocorticoids (dexamethasone) and monoclonal antibodies (REGEN-COV, tocilizumab, sotrovimad, regdanvimad and combination of bamlanivimab and etesevimab).188–192 Despite these successes, small-molecule inhibitors and vaccines are limited in their ability to target “undruggable” portions of the genome. NcRNAs, on the other hand, offer promising targets for therapeutic intervention, as they can regulate genes and affect viral replication and infection in a direct way. Recently, Qu et al.193 reported that circRNARBD-Omicron can induce more effective neutralizing antibodies and immune responses against SARS-CoV-2 variants than mRNA vaccines, indicating that ncRNA-based therapies hold significant potential for future applications.

MiRNA mimics and agomir are widely-used methods to increase the levels of miRNAs which have been downregulated in disease.194–196 MiRNA mimics are designed to have the same sequence as endogenous mature miRNAs, and can increase the levels of mature miRNAs and reorganize their targets (Fig. 3c).197,198 For instance, miR-219 has been recognized as a pivotal function in regulating the oligodendrocyte development, myelination, and remyelination.199 In a demyelinating model induced by Theiler’s murine encephalomyelitis virus, intranasal administration of miR-219 mimics before disease onset markedly improved the disease severity, along with reduction of pro-inflammatory cytokine levels and viral RNA replication.200 This result highlights the potential of host miRNA mimics for the treatment of viral diseases. Moreover, the ease with which miRNA mimics can be synthesized in commercial laboratories increases their availability and accessibility for clinical use.185

In a broader context, therapeutic interventions based on ncRNAs can be classified into two distinct categories: those that modulate transcription at the DNA level, and those that modulate transcription at the RNA level (Fig. 3c). To date, DNA genome-editing tools, such as CRISPR-interference and CRISPR-activation showed exciting efficiency to inhibit or activate ncRNAs expression. In this method, the mutant form of Cas9 is fused with transcriptional repressors or activators of the promoter of specific ncRNAs.201,202 The two main strategies of modulation RNA expression are ASOs and RNA-mediated interference (RNAi) which can inhibit the ncRNAs. The high affinity with the cell membrane and great transfection efficiency making ASOs and RNAi as promising ncRNAs-based inhibitory therapies.203,204 On the other side, circRNAs can sequester virus-associated miRNAs and restrain their bio-accessibility to mRNA, or circRNAs directly target the conserved regions of viral RNA to suppress its propagation.205,206 Thus, it is crucial to fully explore the potential possibility of ncRNAs-based therapeutics for COVID-19 and subsequent disease states.

Conclusion and perspective

This review highlights the significance of host miRNAs, lncRNAs, and circRNAs in the pathogenesis of SARS-CoV-2, providing evidence for the potential clinical value of ncRNAs in the stratification, prediction, and treatment of COVID-19, including long COVID.

Increasing research has demonstrated that viral infections can induce widespread changes in host ncRNAs, which in turn can impact virus invasion and pathogenesis. Recent findings have revealed that the interaction between host miRNAs and RNA viruses can be either direct or indirect.207 In the indirect pathway, viral RNA is recognized by pattern-recognition receptors and Toll-like receptors, leading to IFN signaling cascade activation, which suppress viral replication. These processes may further alter miRNA expression levels with pro-viral or antiviral effects. In the direct pathway, host miRNAs directly bind to various regions of the viral genome such as 5’ UTR, 3’ UTR, or coding regions on different types of RNA viruses like Eastern equine encephalitis virus, primate foamy virus 1, HIV, influenza, Hepatitis C virus, as well as SARS-CoV-2. This direct interaction can result in the inhibition of viral genome translation to suppress viral replication or stabilization of virus RNA to promote replication. Additionally, altered miRNAs may be involved in host immune response and contribute to viral pathogenesis. Similarly, lncRNAs exhibit pleiotropic functions in modulating the pathogenesis of viruses.208 Commonly, lncRNAs regulate viral pathogenesis through several mechanisms, such as modulation of cytoplasmic RNA receptors involved in viral recognition, regulation of IFN genes and IFN-stimulated genes expression leading to either anti- or pro-viral replication properties, and direct modulation of IFN production by binding to the IFN promoter region. While there is a paucity of information about the circRNAs, some studies have highlighted their significance in modulating viral pathogenesis. The primary mechanism by which circRNAs function is through acting as miRNA sponges to influence various processes, including viral replication (e.g., SARS-CoV-1, MER-COV), immune response and inflammation.209 The existence of specific relationships between host ncRNAs and SARS-CoV-2 infection is an intriguing question. However, current research primarily focuses on investigating the dysregulated landscape of host ncRNAs following SARS-CoV-2 infection, with limited wet-lab experiments deciphering the underlying mechanisms behind this relationship. Further studies are warranted to explore their functions and relationships in order to facilitate our understanding of COVID-19 pathogenesis.

Based on the aforementioned findings, a plethora of host ncRNA, particularly miRNAs, have been reorganized as pivotal regulators in modulating pathogenesis to COVID-19. In order to further providing some directions for future studies, we took the miRNAs discussed in the section “SARS-CoV-2 associated ncRNAs” (Supplementary Tables S1–3) as input search, then performed a bioinformatic analysis of the target genes of the miRNA, finding that the immune response and organ deficits, even long COVID, may be promising routines for future investigation. As shown in Fig. 4a, COVID-19-related DEmiRNAs mostly enriched on the TNF pathway with the activation of NF-κB signaling. The aforementioned pathways exhibit a strong association with genes encoding inflammatory factors, including TNF, NF-κB, and inhibitor κB (IκB). In addition, some signaling pathway are highly linked with transcription genes, including transcription factor Jun (JUN), protein c-Fos (FOS), activator protein-1 (AP-1), and cAMP response element-binding protein (CREB). Several genes like HIF1A can interact with JUN and promote the regulatory effect of T cells to enhance virus clearance. This effect can be regulated by the DElncRNAs HIF1A-AS-1. The activation of AP-1 is required to interact with other genes like RORA, which is regulated by DElncRNA RORA-AS-7. The AP-1-associated pathway plays an essential function in controlling T-cell differentiation. Besides, several miRNAs show association with the development of some tissue or organs in the host after SARS-COV-2 infection. We found some miRNAs may play as regulatory factors involved in blood vessel development, which potentially result in the development of cardiovascular disease. Our bioinformatical results also indicate that some DEmiRNAs may regulate the brain development, neural differentiation, and neurogenesis via the interaction with key genes, including DICER1, ATXN1, ATXN1L, and syntaxin-6 (STX6) (Supplementary Fig. S1 and Fig. 4b–d), which potentially contribute to the development of cerebrovascular disease and neurodevelopmental diseases. The future requires further wet-lab experiments to validate their functionality in these processes, surpassing the confines of bioinformatics analysis.Fig. 4 Gene function network analysis of some essential dysregulated miRNAs in COVID-19 cases. a Pathway showing the targets involved in the MAPK and TNF signaling pathway. The color indicates relevant reported times of a gene. b The miRNA-mRNA network in the group of COVID-19 moderate cases vs. healthy controls. c The miRNA-mRNA network in the group of COVID-19 severe cases vs. healthy controls. d The miRNA-mRNA network in the group of COVID-19 severe cases vs. non-severe cases. Different color represents relevant biological function. Green ovals represent immune response related pathways; Orange ovals represent multiorgan deficits related pathways; Purple triangles represent miRNAs

To date, SARS-CoV-2 remains a persistently menacing pathogen to human beings in the foreseeable future. With the emergence of numerous variants of SARS-CoV-2, it is still unclear whether and how the evolutionary trajectories of coronaviruses impact the human genome. Sex can serve as a valuable lens for comprehending this inquiry, as compared to female, significantly disease severity and mortality have been found in male COVID-19 patients.210 Accordingly, elevated expression of virus entry factors, ACE2 and TMPRSS2, was observed in host Sertoli cells and germ cells, indicating a greater impact on males with reproductive disorders in COVID-19.211 Interestingly, our enrichment analysis results of the DEmiRNAs, which also have been reported before, showed that male sex differentiation with master regulatory gene katanin p60 ATPase-containing subunit A-like 1 (KATNAL1) is highly enriched in severe compared to non-severe cases. From a macroscopic perspective, the reproductive disorders following infection may drive some evolutionary adaptations within the human. The ncRNAs derived from the human genome, which are associated with immune response and pathological changes caused by SARS-CoV-2, could serve as evolutionary indicators under substantial selection pressure. In addition to elucidate viral diversity and disease severity, these host ncRNA indicators may also provide insights into the evolutionary trajectories and protection persistence after COVID-19. Further investigation and comparison over an extended temporal scale are imperative to comprehend the potential long-term impact of this selective pressure.

Many gaps are worthy of further exploring in the future. First, there remains a dearth of genome-wide screening of ncRNAs, especially the lncRNAs and circRNAs, expression in individuals of all ages, ranging from children to the elderly, who have been infected with SARS-CoV-2. The use of high-throughput sequencing would be advantageous in uncovering the expression profile of ncRNAs in COVID-19 cases, as well as identifying potential biomarkers and therapeutic targets. Second, multiple variants of SARS-CoV-2 have emerged. Distinct virus subtypes lead to varying symptoms, but little research has examined whether different ncRNA expression is induced.212 Exploring the expression profile of ncRNAs induced by different variants can improve our understanding of their influences. Third, the increasing burden of long COVID and reinfection have resulted in significant challenges, with the pathogenesis and treatments remaining unclear.213–215 Although some hypotheses have been proposed regarding the host ncRNAs in long COVID or reinfection, direct investigations about the functions are lacking. Thus, conducting comprehensive transcriptomic screening and wet-lab experiments of individuals with long COVID or reinfection necessitate further study.

NcRNAs hold significant therapeutic potential for patients. However, challenges such as off-target effects, specificity, and toxicity issues in drug design and delivery systems hinder their clinical translation. With the advancement of sequencing technologies and detection methods, more ncRNAs will emerge from the genome’s dark matter to pave the way for successful translational applications in COVID-19 patients and other human diseases.

Supplementary information

Supplementary_Materials

Supplementary information

The online version contains supplementary material available at 10.1038/s41392-023-01669-0.

Acknowledgements

This work was supported by the National Programs for Brain Science and Brain-like Intelligence Technology of China (nos. 2021ZD0200800 and 2021ZD0200700), National Key Research and Development Program (no. 2021YFC0863700), Natural Science Foundation of Beijing Municipality of China (M23013) and the National Natural Science Foundation of China (nos. 82288101 and 82171514). Images in Figs. 1, 2, and 4 were created with BioRender.com.

Author contributions

L.L. and Y.B. proposed the topic and main idea. X.L., W.X., and T.L. were responsible for the literature search. W.X. and M.Y. were responsible for the data analysis. X.L. and W.X. wrote the initial draft of the manuscript. X.L., W.X., T.L., K.Y., S.C., Y.W., Y.H., Y.B., and L.L. commented on and revised the paper. L.L. and Y.B. finalized the manuscript with contributions from all authors. All authors have read and approved the article.

Competing interests

The authors declare no competing interests.

These authors contributed equally: Xiaoxing Liu, Wandi Xiong
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References

1. Gong Y COVID-19 induced economic slowdown and mental health issues Front. Psychol. 2022 13 777350 10.3389/fpsyg.2022.777350 35310204
Gong, Y. et al. COVID-19 induced economic slowdown and mental health issues. Front. Psychol. 13, 777350 (2022).35310204 10.3389/fpsyg.2022.777350
2. World Economic Situation and Prospects 2023 (United Nations Department of Economic and Social Affairs, the United Nations Conference on Trade and Development, Economic Commission for Africa, Economic Commission for Europe, Economic Commission for Latin America and the Caribbean, Economic and Social Commission for Asia and the Pacific, Economic and Social Commission for Western Asia, and the United Nations World Tourism Organization, 2023).
3. DeGrace MM Defining the risk of SARS-CoV-2 variants on immune protection Nature 2022 605 640 652 10.1038/s41586-022-04690-5 35361968
DeGrace, M. M. et al. Defining the risk of SARS-CoV-2 variants on immune protection. Nature 605, 640–652 (2022).35361968 10.1038/s41586-022-04690-5
4. Jackson CB Farzan M Chen B Choe H Mechanisms of SARS-CoV-2 entry into cells Nat. Rev. Mol. Cell. Biol. 2022 23 3 20 10.1038/s41580-021-00418-x 34611326
Jackson, C. B., Farzan, M., Chen, B. & Choe, H. Mechanisms of SARS-CoV-2 entry into cells. Nat. Rev. Mol. Cell. Biol. 23, 3–20 (2022).34611326 10.1038/s41580-021-00418-x
5. Mehta P COVID-19: consider cytokine storm syndromes and immunosuppression Lancet 2020 395 1033 1034 10.1016/S0140-6736(20)30628-0 32192578
Mehta, P. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395, 1033–1034 (2020).32192578 10.1016/S0140-6736(20)30628-0
6. Wiersinga WJ Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review J. Am. Med. Assoc. 2020 324 782 793 10.1001/jama.2020.12839
Wiersinga, W. J. et al. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. J. Am. Med. Assoc. 324, 782–793 (2020).10.1001/jama.2020.12839
7. Merad M Blish CA Sallusto F Iwasaki A The immunology and immunopathology of COVID-19 Science 2022 375 1122 1127 10.1126/science.abm8108 35271343
Merad, M., Blish, C. A., Sallusto, F. & Iwasaki, A. The immunology and immunopathology of COVID-19. Science 375, 1122–1127 (2022).35271343 10.1126/science.abm8108
8. Nalbandian A Post-acute COVID-19 syndrome Nat. Med. 2021 27 601 615 10.1038/s41591-021-01283-z 33753937
Nalbandian, A. et al. Post-acute COVID-19 syndrome. Nat. Med. 27, 601–615 (2021).33753937 10.1038/s41591-021-01283-z
9. Zeng N A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action Mol. Psychiatry 2022 28 423 433 10.1038/s41380-022-01614-7 35668159
Zeng, N. et al. A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action. Mol. Psychiatry 28, 423–433 (2022).35668159 10.1038/s41380-022-01614-7
10. Slack FJ Chinnaiyan AM The role of non-coding RNAs in oncology Cell 2019 179 1033 1055 10.1016/j.cell.2019.10.017 31730848
Slack, F. J. & Chinnaiyan, A. M. The role of non-coding RNAs in oncology. Cell 179, 1033–1055 (2019).31730848 10.1016/j.cell.2019.10.017
11. Beermann J Piccoli MT Viereck J Thum T Non-coding RNAs in development and disease: Background, mechanisms, and therapeutic approaches Physiol. Rev. 2016 96 1297 1325 10.1152/physrev.00041.2015 27535639
Beermann, J., Piccoli, M. T., Viereck, J. & Thum, T. Non-coding RNAs in development and disease: Background, mechanisms, and therapeutic approaches. Physiol. Rev. 96, 1297–1325 (2016).27535639 10.1152/physrev.00041.2015
12. Statello L Guo CJ Chen LL Huarte M Gene regulation by long non-coding RNAs and its biological functions Nat. Rev. Mol. Cell. Biol. 2021 22 96 118 10.1038/s41580-020-00315-9 33353982
Statello, L., Guo, C. J., Chen, L. L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell. Biol. 22, 96–118 (2021).33353982 10.1038/s41580-020-00315-9
13. Memczak S Circular RNAs are a large class of animal RNAs with regulatory potency Nature 2013 495 333 338 10.1038/nature11928 23446348
Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).23446348 10.1038/nature11928
14. Kopp F Mendell JT Functional classification and experimental dissection of long noncoding RNAs Cell 2018 172 393 407 10.1016/j.cell.2018.01.011 29373828
Kopp, F. & Mendell, J. T. Functional classification and experimental dissection of long noncoding RNAs. Cell 172, 393–407 (2018).29373828 10.1016/j.cell.2018.01.011
15. Chen LL The expanding regulatory mechanisms and cellular functions of circular RNAs Nat. Rev. Mol. Cell. Biol. 2020 21 475 490 10.1038/s41580-020-0243-y 32366901
Chen, L. L. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat. Rev. Mol. Cell. Biol. 21, 475–490 (2020).32366901 10.1038/s41580-020-0243-y
16. Chen Y Li Z Chen X Zhang S Long non-coding RNAs: from disease code to drug role Acta Pharm. Sin. B. 2021 11 340 354 10.1016/j.apsb.2020.10.001 33643816
Chen, Y., Li, Z., Chen, X. & Zhang, S. Long non-coding RNAs: from disease code to drug role. Acta Pharm. Sin. B. 11, 340–354 (2021).33643816 10.1016/j.apsb.2020.10.001
17. Zhang X Viral circular RNAs and their possible roles in virus-host interaction Front. Immunol. 2022 13 939768 10.3389/fimmu.2022.939768 35784275
Zhang, X. et al. Viral circular RNAs and their possible roles in virus-host interaction. Front. Immunol. 13, 939768 (2022).35784275 10.3389/fimmu.2022.939768
18. Mishra R Kumar A Ingle H Kumar H The interplay between viral-derived miRNAs and host immunity during infection Front. Immunol. 2019 10 3079 10.3389/fimmu.2019.03079 32038626
Mishra, R., Kumar, A., Ingle, H. & Kumar, H. The interplay between viral-derived miRNAs and host immunity during infection. Front. Immunol. 10, 3079 (2019).32038626 10.3389/fimmu.2019.03079
19. Li Z Viral long non-coding RNA regulates virus life-cycle and pathogenicity Mol. Biol. Rep. 2022 49 6693 6700 10.1007/s11033-022-07268-6 35301646
Li, Z. et al. Viral long non-coding RNA regulates virus life-cycle and pathogenicity. Mol. Biol. Rep. 49, 6693–6700 (2022).35301646 10.1007/s11033-022-07268-6
20. Tycowski KT Viral noncoding RNAs: more surprises Genes. Dev. 2015 29 567 584 10.1101/gad.259077.115 25792595
Tycowski, K. T. et al. Viral noncoding RNAs: more surprises. Genes. Dev. 29, 567–584 (2015).25792595 10.1101/gad.259077.115
21. Cai Z Identification and characterization of circRNAs encoded by MERS-CoV, SARS-CoV-1 and SARS-CoV-2 Brief Bioinforma 2021 22 1297 1308 10.1093/bib/bbaa334
Cai, Z. et al. Identification and characterization of circRNAs encoded by MERS-CoV, SARS-CoV-1 and SARS-CoV-2. Brief Bioinforma 22, 1297–1308 (2021).10.1093/bib/bbaa334
22. Aydemir MN Computationally predicted SARS-COV-2 encoded microRNAs target NFKB, JAK/STAT and TGFB signaling pathways Gene Rep. 2021 22 101012 10.1016/j.genrep.2020.101012 33398248
Aydemir, M. N. et al. Computationally predicted SARS-COV-2 encoded microRNAs target NFKB, JAK/STAT and TGFB signaling pathways. Gene Rep. 22, 101012 (2021).33398248 10.1016/j.genrep.2020.101012
23. Musazzi, L. et al. Stress, microRNAs, and stress-related psychiatric disorders: an overview. Mol. Psychiatry10.1038/s41380-023-02139-3 (2023).
24. Roggendorf M Rational use of diagnostic tools in hepatitis C J. Hepatol. 1996 24 26 34 8836886
Roggendorf, M. et al. Rational use of diagnostic tools in hepatitis C. J. Hepatol. 24, 26–34 (1996).8836886
25. Foley KP Leonard MW Engel JD Quantitation of RNA using the polymerase chain reaction Trends Genet. 1993 9 380 385 10.1016/0168-9525(93)90137-7 7508648
Foley, K. P., Leonard, M. W. & Engel, J. D. Quantitation of RNA using the polymerase chain reaction. Trends Genet. 9, 380–385 (1993).7508648 10.1016/0168-9525(93)90137-7
26. Vogelstein B Kinzler KW Digital PCR Proc. Natl. Acad. Sci. USA 1999 96 9236 9241 10.1073/pnas.96.16.9236 10430926
Vogelstein, B. & Kinzler, K. W. Digital PCR. Proc. Natl. Acad. Sci. USA 96, 9236–9241 (1999).10430926 10.1073/pnas.96.16.9236
27. Kojabad AA Droplet digital PCR of viral DNA/RNA, current progress, challenges, and future perspectives J. Med. Virol. 2021 93 4182 4197 10.1002/jmv.26846 33538349
Kojabad, A. A. et al. Droplet digital PCR of viral DNA/RNA, current progress, challenges, and future perspectives. J. Med. Virol. 93, 4182–4197 (2021).33538349 10.1002/jmv.26846
28. Stark R Grzelak M Hadfield J RNA sequencing: the teenage years Nat. Rev. Genet. 2019 20 631 656 10.1038/s41576-019-0150-2 31341269
Stark, R., Grzelak, M. & Hadfield, J. RNA sequencing: the teenage years. Nat. Rev. Genet. 20, 631–656 (2019).31341269 10.1038/s41576-019-0150-2
29. Zhou Y Encoding method of single-cell spatial transcriptomics sequencing Int. J. Biol. Sci. 2020 16 2663 2674 10.7150/ijbs.43887 32792863
Zhou, Y. et al. Encoding method of single-cell spatial transcriptomics sequencing. Int. J. Biol. Sci. 16, 2663–2674 (2020).32792863 10.7150/ijbs.43887
30. Bagheri-Hosseinabadi Z The relationship between serum levels of interleukin-2 and IL-8 with circulating microRNA-10b in patients with COVID-19 Iran J. Immunol. 2021 18 65 73 33787515
Bagheri-Hosseinabadi, Z. et al. The relationship between serum levels of interleukin-2 and IL-8 with circulating microRNA-10b in patients with COVID-19. Iran J. Immunol. 18, 65–73 (2021).33787515
31. Parray A SnoRNAs and miRNAs networks underlying COVID-19 disease severity Vaccines 2021 9 1056 10.3390/vaccines9101056 34696164
Parray, A. et al. SnoRNAs and miRNAs networks underlying COVID-19 disease severity. Vaccines 9, 1056 (2021).34696164 10.3390/vaccines9101056
32. Agwa SHA In silico identification and clinical validation of a novel long non-coding RNA/mRNA/miRNA molecular network for potential biomarkers for discriminating SARS CoV-2 infection severity Cells 2021 10 3098 10.3390/cells10113098 34831321
Agwa, S. H. A. et al. In silico identification and clinical validation of a novel long non-coding RNA/mRNA/miRNA molecular network for potential biomarkers for discriminating SARS CoV-2 infection severity. Cells 10, 3098 (2021).34831321 10.3390/cells10113098
33. Liu X SARS-CoV-2 causes a significant stress response mediated by small RNAs in the blood of COVID-19 patients Mol. Ther. Nucleic Acids 2022 27 751 762 10.1016/j.omtn.2021.12.034 35003892
Liu, X. et al. SARS-CoV-2 causes a significant stress response mediated by small RNAs in the blood of COVID-19 patients. Mol. Ther. Nucleic Acids 27, 751–762 (2022).35003892 10.1016/j.omtn.2021.12.034
34. Wu Y A study of differential circRNA and lncRNA expressions in COVID-19-infected peripheral blood Sci. Rep. 2021 11 7991 10.1038/s41598-021-86134-0 33846375
Wu, Y. et al. A study of differential circRNA and lncRNA expressions in COVID-19-infected peripheral blood. Sci. Rep. 11, 7991 (2021).33846375 10.1038/s41598-021-86134-0
35. Wu W Changes of small non-coding RNAs by severe acute respiratory syndrome coronavirus 2 infection Front. Mol. Biosci. 2021 9 821137 10.3389/fmolb.2022.821137
Wu, W. et al. Changes of small non-coding RNAs by severe acute respiratory syndrome coronavirus 2 infection. Front. Mol. Biosci. 9, 821137 (2021).10.3389/fmolb.2022.821137
36. Rodrigues AC NEAT1 and MALAT1 are highly expressed in saliva and nasopharyngeal swab samples of COVID-19 patients Mol. Oral. Microbiol. 2021 36 291 294 10.1111/omi.12351 34463043
Rodrigues, A. C. et al. NEAT1 and MALAT1 are highly expressed in saliva and nasopharyngeal swab samples of COVID-19 patients. Mol. Oral. Microbiol. 36, 291–294 (2021).34463043 10.1111/omi.12351
37. McDonald JT Role of miR-2392 in driving SARS-CoV-2 infection Cell Rep. 2021 37 109839 10.1016/j.celrep.2021.109839 34624208
McDonald, J. T. et al. Role of miR-2392 in driving SARS-CoV-2 infection. Cell Rep. 37, 109839 (2021).34624208 10.1016/j.celrep.2021.109839
38. Mi B SARS-CoV-2-induced overexpression of miR-4485 suppresses osteogenic differentiation and impairs fracture healing Int. J. Biol. Sci. 2021 17 1277 1288 10.7150/ijbs.56657 33867845
Mi, B. et al. SARS-CoV-2-induced overexpression of miR-4485 suppresses osteogenic differentiation and impairs fracture healing. Int. J. Biol. Sci. 17, 1277–1288 (2021).33867845 10.7150/ijbs.56657
39. Reinhold D The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation J. Neuroinflammation 2023 20 30 10.1186/s12974-023-02711-2 36759861
Reinhold, D. et al. The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation. J. Neuroinflammation 20, 30 (2023).36759861 10.1186/s12974-023-02711-2
40. Centa A Deregulated miRNA expression is associated with endothelial dysfunction in post-mortem lung biopsies of COVID-19 patients Am. J. Physiol. Lung Cell. Mol. Physiol. 2021 320 L405 L412 10.1152/ajplung.00457.2020 33651636
Centa, A. et al. Deregulated miRNA expression is associated with endothelial dysfunction in post-mortem lung biopsies of COVID-19 patients. Am. J. Physiol. Lung Cell. Mol. Physiol. 320, L405–L412 (2021).33651636 10.1152/ajplung.00457.2020
41. Abbasi-Kolli M The expression patterns of MALAT-1, NEAT-1, THRIL, and miR-155-5p in the acute to the post-acute phase of COVID-19 disease Braz. J. Infect. Dis. 2022 26 102354 10.1016/j.bjid.2022.102354 35500644
Abbasi-Kolli, M. et al. The expression patterns of MALAT-1, NEAT-1, THRIL, and miR-155-5p in the acute to the post-acute phase of COVID-19 disease. Braz. J. Infect. Dis. 26, 102354 (2022).35500644 10.1016/j.bjid.2022.102354
42. Zheng HY Longitudinal transcriptome analyses show robust T cell immunity during recovery from COVID-19 Signal Transduct. Target. Ther. 2020 5 294 10.1038/s41392-020-00457-4 33361761
Zheng, H. Y. et al. Longitudinal transcriptome analyses show robust T cell immunity during recovery from COVID-19. Signal Transduct. Target. Ther. 5, 294 (2020).33361761 10.1038/s41392-020-00457-4
43. Fernandez-Pato A Plasma miRNA profile at COVID-19 onset predicts severity status and mortality Emerg. Microbes Infect. 2022 11 676 688 10.1080/22221751.2022.2038021 35130828
Fernandez-Pato, A. et al. Plasma miRNA profile at COVID-19 onset predicts severity status and mortality. Emerg. Microbes Infect. 11, 676–688 (2022).35130828 10.1080/22221751.2022.2038021
44. Duecker RP The MiR-320 family is strongly downregulated in patients with COVID-19 induced severe respiratory failure Int. J. Mol. Sci. 2021 22 10351 10.3390/ijms221910351 34638691
Duecker, R. P. et al. The MiR-320 family is strongly downregulated in patients with COVID-19 induced severe respiratory failure. Int. J. Mol. Sci. 22, 10351 (2021).34638691 10.3390/ijms221910351
45. Donyavi T Acute and post-acute phase of COVID-19: analyzing expression patterns of miRNA-29a-3p, 146a-3p, 155-5p, and let-7b-3p in PBMC Int. Immunopharmacol. 2021 97 107641 10.1016/j.intimp.2021.107641 33895478
Donyavi, T. et al. Acute and post-acute phase of COVID-19: analyzing expression patterns of miRNA-29a-3p, 146a-3p, 155-5p, and let-7b-3p in PBMC. Int. Immunopharmacol. 97, 107641 (2021).33895478 10.1016/j.intimp.2021.107641
46. Garg A Circulating cardiovascular microRNAs in critically ill COVID-19 patients Eur. J. Heart Fail 2021 23 468 475 10.1002/ejhf.2096 33421274
Garg, A. et al. Circulating cardiovascular microRNAs in critically ill COVID-19 patients. Eur. J. Heart Fail 23, 468–475 (2021).33421274 10.1002/ejhf.2096
47. Giuliani A Circulating miR-320b and miR-483-5p levels are associated with COVID-19 in-hospital mortality Mech. Ageing Dev. 2022 202 111636 10.1016/j.mad.2022.111636 35122770
Giuliani, A. et al. Circulating miR-320b and miR-483-5p levels are associated with COVID-19 in-hospital mortality. Mech. Ageing Dev. 202, 111636 (2022).35122770 10.1016/j.mad.2022.111636
48. Wilson JC Integrated miRNA/cytokine/chemokine profiling reveals severity-associated step changes and principal correlates of fatality in COVID-19 iScience 2022 25 103672 10.1016/j.isci.2021.103672 34957382
Wilson, J. C. et al. Integrated miRNA/cytokine/chemokine profiling reveals severity-associated step changes and principal correlates of fatality in COVID-19. iScience 25, 103672 (2022).34957382 10.1016/j.isci.2021.103672
49. Gutmann C Association of cardiometabolic microRNAs with COVID-19 severity and mortality Cardiovasc. Res 2022 118 461 474 10.1093/cvr/cvab338 34755842
Gutmann, C. et al. Association of cardiometabolic microRNAs with COVID-19 severity and mortality. Cardiovasc. Res 118, 461–474 (2022).34755842 10.1093/cvr/cvab338
50. Tang H The noncoding and coding transcriptional landscape of the peripheral immune response in patients with COVID-19 Clin. Transl. Med. 2020 10 e200 10.1002/ctm2.200 33135345
Tang, H. et al. The noncoding and coding transcriptional landscape of the peripheral immune response in patients with COVID-19. Clin. Transl. Med. 10, e200 (2020).33135345 10.1002/ctm2.200
51. Wu J Expression of plasma IFN signaling-related miRNAs during acute SARS-CoV-2 infection and its association with RBD-IgG antibody response Virol. J. 2021 18 244 10.1186/s12985-021-01717-7 34876159
Wu, J. et al. Expression of plasma IFN signaling-related miRNAs during acute SARS-CoV-2 infection and its association with RBD-IgG antibody response. Virol. J. 18, 244 (2021).34876159 10.1186/s12985-021-01717-7
52. Farr RJ Altered microRNA expression in COVID-19 patients enables identification of SARS-CoV-2 infection PLoS. Pathog. 2021 17 e1009759 10.1371/journal.ppat.1009759 34320031
Farr, R. J. et al. Altered microRNA expression in COVID-19 patients enables identification of SARS-CoV-2 infection. PLoS. Pathog. 17, e1009759 (2021).34320031 10.1371/journal.ppat.1009759
53. Li CX Whole-transcriptome RNA sequencing reveals significant differentially expressed mRNAs, miRNAs, and lncRNAs and related regulating biological pathways in the peripheral blood of COVID-19 patients Mediators Inflamm. 2021 2021 6635925 10.1155/2021/6635925 33833618
Li, C. X. et al. Whole-transcriptome RNA sequencing reveals significant differentially expressed mRNAs, miRNAs, and lncRNAs and related regulating biological pathways in the peripheral blood of COVID-19 patients. Mediators Inflamm. 2021, 6635925 (2021).33833618 10.1155/2021/6635925
54. Cheng J Risk stratification by long non-coding RNAs profiling in COVID-19 patients J. Cell. Mol. Med. 2021 25 4753 4764 10.1111/jcmm.16444 33759345
Cheng, J. et al. Risk stratification by long non-coding RNAs profiling in COVID-19 patients. J. Cell. Mol. Med. 25, 4753–4764 (2021).33759345 10.1111/jcmm.16444
55. Rombauts A Dynamics of gene expression profiling and identification of high-risk patients for severe COVID-19 Biomedicines 2023 11 1348 10.3390/biomedicines11051348 37239019
Rombauts, A. et al. Dynamics of gene expression profiling and identification of high-risk patients for severe COVID-19. Biomedicines 11, 1348 (2023).37239019 10.3390/biomedicines11051348
56. Bowe B Xie Y Al-Aly Z Acute and postacute sequelae associated with SARS-CoV-2 reinfection Nat. Med. 2022 28 2398 2405 10.1038/s41591-022-02051-3 36357676
Bowe, B., Xie, Y. & Al-Aly, Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection. Nat. Med. 28, 2398–2405 (2022).36357676 10.1038/s41591-022-02051-3
57. Aznaourova M Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19 Proc. Natl. Acad. Sci. USA 2022 119 e2120680119 10.1073/pnas.2120680119 35998224
Aznaourova, M. et al. Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19. Proc. Natl. Acad. Sci. USA 119, e2120680119 (2022).35998224 10.1073/pnas.2120680119
58. Yang M Differential host circRNA expression profiles in human lung epithelial cells infected with SARS-CoV-2 Infect. Genet. Evol. 2021 93 104923 10.1016/j.meegid.2021.104923 34004360
Yang, M. et al. Differential host circRNA expression profiles in human lung epithelial cells infected with SARS-CoV-2. Infect. Genet. Evol. 93, 104923 (2021).34004360 10.1016/j.meegid.2021.104923
59. Shang, R., Lee, S., Senavirathne, G. & Lai, E. C. MicroRNAs in action: biogenesis, function and regulation. Nat. Rev. Genet. 10.1038/s41576-023-00611-y (2023).
60. Kristensen LS The biogenesis, biology and characterization of circular RNAs Nat. Rev. Genet. 2019 20 675 691 10.1038/s41576-019-0158-7 31395983
Kristensen, L. S. et al. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 20, 675–691 (2019).31395983 10.1038/s41576-019-0158-7
61. Skalsky RL Cullen BR Viruses, microRNAs, and host interactions Annu. Rev. Microbiol. 2010 64 123 141 10.1146/annurev.micro.112408.134243 20477536
Skalsky, R. L. & Cullen, B. R. Viruses, microRNAs, and host interactions. Annu. Rev. Microbiol. 64, 123–141 (2010).20477536 10.1146/annurev.micro.112408.134243
62. Libri V Miesen P van Rij RP Buck AH Regulation of microRNA biogenesis and turnover by animals and their viruses Cell. Mol. Life. Sci. 2013 70 3525 3544 10.1007/s00018-012-1257-1 23354060
Libri, V., Miesen, P., van Rij, R. P. & Buck, A. H. Regulation of microRNA biogenesis and turnover by animals and their viruses. Cell. Mol. Life. Sci. 70, 3525–3544 (2013).23354060 10.1007/s00018-012-1257-1
63. Arora S Unravelling host-pathogen interactions: ceRNA network in SARS-CoV-2 infection (COVID-19) Gene 2020 762 145057 10.1016/j.gene.2020.145057 32805314
Arora, S. et al. Unravelling host-pathogen interactions: ceRNA network in SARS-CoV-2 infection (COVID-19). Gene 762, 145057 (2020).32805314 10.1016/j.gene.2020.145057
64. Garnier N Genes involved in miRNA biogenesis are not downregulated in SARS-COV-2 infection Viruses 2023 15 1177 10.3390/v15051177 37243263
Garnier, N. et al. Genes involved in miRNA biogenesis are not downregulated in SARS-COV-2 infection. Viruses 15, 1177 (2023).37243263 10.3390/v15051177
65. Hoffmann M SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Cell 2020 181 271 280 e278 10.1016/j.cell.2020.02.052 32142651
Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280 e278 (2020).32142651 10.1016/j.cell.2020.02.052
66. Xu Z Pathological findings of COVID-19 associated with acute respiratory distress syndrome Lancet Respir. Med. 2020 8 420 422 10.1016/S2213-2600(20)30076-X 32085846
Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420–422 (2020).32085846 10.1016/S2213-2600(20)30076-X
67. Attaway AH Severe covid-19 pneumonia: pathogenesis and clinical management BMJ 2021 372 n436 10.1136/bmj.n436 33692022
Attaway, A. H. et al. Severe covid-19 pneumonia: pathogenesis and clinical management. BMJ 372, n436 (2021).33692022 10.1136/bmj.n436
68. Gupta A Extrapulmonary manifestations of COVID-19 Nat. Med. 2020 26 1017 1032 10.1038/s41591-020-0968-3 32651579
Gupta, A. et al. Extrapulmonary manifestations of COVID-19. Nat. Med. 26, 1017–1032 (2020).32651579 10.1038/s41591-020-0968-3
69. Glowacka I Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response J. Virol. 2011 85 4122 4134 10.1128/JVI.02232-10 21325420
Glowacka, I. et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J. Virol. 85, 4122–4134 (2011).21325420 10.1128/JVI.02232-10
70. Matsuyama S Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2 J. Virol. 2010 84 12658 12664 10.1128/JVI.01542-10 20926566
Matsuyama, S. et al. Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. J. Virol. 84, 12658–12664 (2010).20926566 10.1128/JVI.01542-10
71. Huang IC SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells J. Biol. Chem. 2006 281 3198 3203 10.1074/jbc.M508381200 16339146
Huang, I. C. et al. SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. J. Biol. Chem. 281, 3198–3203 (2006).16339146 10.1074/jbc.M508381200
72. Simmons G Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry Proc. Natl. Acad. Sci. USA 2005 102 11876 11881 10.1073/pnas.0505577102 16081529
Simmons, G. et al. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc. Natl. Acad. Sci. USA 102, 11876–11881 (2005).16081529 10.1073/pnas.0505577102
73. Thomas G Furin at the cutting edge: From protein traffic to embryogenesis and disease Nat. Rev. Mol. Cell. Biol. 2002 3 753 766 10.1038/nrm934 12360192
Thomas, G. Furin at the cutting edge: From protein traffic to embryogenesis and disease. Nat. Rev. Mol. Cell. Biol. 3, 753–766 (2002).12360192 10.1038/nrm934
74. Hoffmann M Kleine-Weber H Pohlmann S A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells Mol. Cell. 2020 78 779 784 10.1016/j.molcel.2020.04.022 32362314
Hoffmann, M., Kleine-Weber, H. & Pohlmann, S. A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol. Cell. 78, 779–784 (2020).32362314 10.1016/j.molcel.2020.04.022
75. Johnson BA Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis Nature 2021 591 293 299 10.1038/s41586-021-03237-4 33494095
Johnson, B. A. et al. Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature 591, 293–299 (2021).33494095 10.1038/s41586-021-03237-4
76. Diallo I Altered microRNA transcriptome in cultured human airway cells upon infection with SARS-CoV-2 Viruses 2023 15 496 10.3390/v15020496 36851710
Diallo, I. et al. Altered microRNA transcriptome in cultured human airway cells upon infection with SARS-CoV-2. Viruses 15, 496 (2023).36851710 10.3390/v15020496
77. Datta PK SARS-CoV-2 pandemic and research gaps: understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy Theranostics 2020 10 7448 7464 10.7150/thno.48076 32642005
Datta, P. K. et al. SARS-CoV-2 pandemic and research gaps: understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy. Theranostics 10, 7448–7464 (2020).32642005 10.7150/thno.48076
78. Sungnak W SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes Nat. Med. 2020 26 681 687 10.1038/s41591-020-0868-6 32327758
Sungnak, W. et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat. Med. 26, 681–687 (2020).32327758 10.1038/s41591-020-0868-6
79. Hou YJ SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract Cell 2020 182 429 446 e414 10.1016/j.cell.2020.05.042 32526206
Hou, Y. J. et al. SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell 182, 429–446 e414 (2020).32526206 10.1016/j.cell.2020.05.042
80. Ziegler CGK SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues Cell 2020 181 1016 1035 10.1016/j.cell.2020.04.035 32413319
Ziegler, C. G. K. et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 181, 1016–1035 (2020).32413319 10.1016/j.cell.2020.04.035
81. Khan AT A computational and bioinformatic analysis of ACE2: an elucidation of its dual role in COVID-19 pathology and finding its associated partners as potential therapeutic targets J. Biomol. Struct. Dyn. 2022 40 1813 1829 10.1080/07391102.2020.1833760 33073716
Khan, A. T. et al. A computational and bioinformatic analysis of ACE2: an elucidation of its dual role in COVID-19 pathology and finding its associated partners as potential therapeutic targets. J. Biomol. Struct. Dyn. 40, 1813–1829 (2022).33073716 10.1080/07391102.2020.1833760
82. Gerard L Increased angiotensin-converting enzyme 2 and loss of alveolar type ii cells in COVID-19-related acute respiratory distress syndrome Am. J. Respir. Crit. Care Med. 2021 204 1024 1034 10.1164/rccm.202012-4461OC 34449302
Gerard, L. et al. Increased angiotensin-converting enzyme 2 and loss of alveolar type ii cells in COVID-19-related acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 204, 1024–1034 (2021).34449302 10.1164/rccm.202012-4461OC
83. Nersisyan S Potential role of cellular miRNAs in coronavirus-host interplay PeerJ 2020 8 e9994 10.7717/peerj.9994 32983652
Nersisyan, S. et al. Potential role of cellular miRNAs in coronavirus-host interplay. PeerJ 8, e9994 (2020).32983652 10.7717/peerj.9994
84. Shapira T A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic Nature 2022 605 340 348 10.1038/s41586-022-04661-w 35344983
Shapira, T. et al. A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature 605, 340–348 (2022).35344983 10.1038/s41586-022-04661-w
85. Chen H SARS-CoV-2 activates lung epithelial cell proinflammatory signaling and leads to immune dysregulation in COVID-19 patients EBioMedicine 2021 70 103500 10.1016/j.ebiom.2021.103500 34311326
Chen, H. et al. SARS-CoV-2 activates lung epithelial cell proinflammatory signaling and leads to immune dysregulation in COVID-19 patients. EBioMedicine 70, 103500 (2021).34311326 10.1016/j.ebiom.2021.103500
86. Matarese A Gambardella J Sardu C Santulli G miR-98 regulates TMPRSS2 expression in human endothelial cells: key implications for COVID-19 Biomedicines 2020 8 462 10.3390/biomedicines8110462 33143053
Matarese, A., Gambardella, J., Sardu, C. & Santulli, G. miR-98 regulates TMPRSS2 expression in human endothelial cells: key implications for COVID-19. Biomedicines 8, 462 (2020).33143053 10.3390/biomedicines8110462
87. Liang Y Circulating microRNAs as emerging regulators of COVID-19 Theranostics 2023 13 125 147 10.7150/thno.78164 36593971
Liang, Y. et al. Circulating microRNAs as emerging regulators of COVID-19. Theranostics 13, 125–147 (2023).36593971 10.7150/thno.78164
88. de Gonzalo-Calvo D Circulating microRNA profiles predict the severity of COVID-19 in hospitalized patients Transl. Res. 2021 236 147 159 10.1016/j.trsl.2021.05.004 34048985
de Gonzalo-Calvo, D. et al. Circulating microRNA profiles predict the severity of COVID-19 in hospitalized patients. Transl. Res. 236, 147–159 (2021).34048985 10.1016/j.trsl.2021.05.004
89. Chen L Zhong L Genomics functional analysis and drug screening of SARS-CoV-2 Genes Dis. 2020 7 542 550 10.1016/j.gendis.2020.04.002 32363223
Chen, L. & Zhong, L. Genomics functional analysis and drug screening of SARS-CoV-2. Genes Dis. 7, 542–550 (2020).32363223 10.1016/j.gendis.2020.04.002
90. Cong Y Nucleocapsid protein recruitment to replication-transcription complexes plays a crucial role in coronaviral life cycle J. Virol. 2020 94 e01925 19 10.1128/JVI.01925-19 31776274
Cong, Y. et al. Nucleocapsid protein recruitment to replication-transcription complexes plays a crucial role in coronaviral life cycle. J. Virol. 94, e01925–19 (2020).31776274 10.1128/JVI.01925-19
91. Arunachalam PS Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans Science 2020 369 1210 1220 10.1126/science.abc6261 32788292
Arunachalam, P. S. et al. Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science 369, 1210–1220 (2020).32788292 10.1126/science.abc6261
92. Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370, eabd4585 (2020).
93. Blanco-Melo D Imbalanced host response to SARS-CoV-2 drives development of COVID-19 Cell 2020 181 1036 1045 e1039 10.1016/j.cell.2020.04.026 32416070
Blanco-Melo, D. et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 181, 1036–1045 e1039 (2020).32416070 10.1016/j.cell.2020.04.026
94. Oran DP Topol EJ Prevalence of asymptomatic SARS-CoV-2 infection: a narrative review Ann. Intern. Med. 2020 173 362 367 10.7326/M20-3012 32491919
Oran, D. P. & Topol, E. J. Prevalence of asymptomatic SARS-CoV-2 infection: a narrative review. Ann. Intern. Med. 173, 362–367 (2020).32491919 10.7326/M20-3012
95. Sette A Crotty S Adaptive immunity to SARS-CoV-2 and COVID-19 Cell 2021 184 861 880 10.1016/j.cell.2021.01.007 33497610
Sette, A. & Crotty, S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 184, 861–880 (2021).33497610 10.1016/j.cell.2021.01.007
96. Ramasamy S Subbian S Critical determinants of cytokine storm and type i interferon response in COVID-19 pathogenesis Clin. Microbiol. Rev. 2021 34 e00299 00220 33980688
Ramasamy, S. & Subbian, S. Critical determinants of cytokine storm and type i interferon response in COVID-19 pathogenesis. Clin. Microbiol. Rev. 34, e00299–00220 (2021).33980688
97. Brodin P Immune determinants of COVID-19 disease presentation and severity Nat. Med. 2021 27 28 33 10.1038/s41591-020-01202-8 33442016
Brodin, P. Immune determinants of COVID-19 disease presentation and severity. Nat. Med. 27, 28–33 (2021).33442016 10.1038/s41591-020-01202-8
98. Lodish HF Zhou B Liu G Chen CZ Micromanagement of the immune system by microRNAs Nat. Rev. Immunol. 2008 8 120 130 10.1038/nri2252 18204468
Lodish, H. F., Zhou, B., Liu, G. & Chen, C. Z. Micromanagement of the immune system by microRNAs. Nat. Rev. Immunol. 8, 120–130 (2008).18204468 10.1038/nri2252
99. Atianand MK Caffrey DR Fitzgerald KA Immunobiology of long noncoding RNAs Annu. Rev. Immunol. 2017 35 177 198 10.1146/annurev-immunol-041015-055459 28125358
Atianand, M. K., Caffrey, D. R. & Fitzgerald, K. A. Immunobiology of long noncoding RNAs. Annu. Rev. Immunol. 35, 177–198 (2017).28125358 10.1146/annurev-immunol-041015-055459
100. Yan L Chen YG Circular RNAs in immune response and viral infection Trends Biochem. Sci. 2020 45 1022 1034 10.1016/j.tibs.2020.08.006 32900574
Yan, L. & Chen, Y. G. Circular RNAs in immune response and viral infection. Trends Biochem. Sci. 45, 1022–1034 (2020).32900574 10.1016/j.tibs.2020.08.006
101. Zhang S The miRNA: a small but powerful RNA for COVID-19 Brief. Bioinforma 2021 22 1137 1149 10.1093/bib/bbab062
Zhang, S. et al. The miRNA: a small but powerful RNA for COVID-19. Brief. Bioinforma 22, 1137–1149 (2021).10.1093/bib/bbab062
102. Wood ER The role of phosphodiesterase 12 (PDE12) as a negative regulator of the innate immune response and the discovery of antiviral inhibitors J. Biol. Chem. 2015 290 19681 19696 10.1074/jbc.M115.653113 26055709
Wood, E. R. et al. The role of phosphodiesterase 12 (PDE12) as a negative regulator of the innate immune response and the discovery of antiviral inhibitors. J. Biol. Chem. 290, 19681–19696 (2015).26055709 10.1074/jbc.M115.653113
103. Hadjadj J Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients Science 2020 369 718 724 10.1126/science.abc6027 32661059
Hadjadj, J. et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369, 718–724 (2020).32661059 10.1126/science.abc6027
104. Moazzam-Jazi M Interplay between SARS-CoV-2 and human long non-coding RNAs J. Cell. Mol. Med. 2021 25 5823 5827 10.1111/jcmm.16596 33969601
Moazzam-Jazi, M. et al. Interplay between SARS-CoV-2 and human long non-coding RNAs. J. Cell. Mol. Med. 25, 5823–5827 (2021).33969601 10.1111/jcmm.16596
105. Ayaz H Mapping CircRNA-miRNA-mRNA regulatory axis identifies hsa_circ_0080942 and hsa_circ_0080135 as a potential theranostic agents for SARS-CoV-2 infection PLoS. ONE 2023 18 e0283589 10.1371/journal.pone.0283589 37053191
Ayaz, H. et al. Mapping CircRNA-miRNA-mRNA regulatory axis identifies hsa_circ_0080942 and hsa_circ_0080135 as a potential theranostic agents for SARS-CoV-2 infection. PLoS. ONE 18, e0283589 (2023).37053191 10.1371/journal.pone.0283589
106. Lu L Zhang H Dauphars DJ He YW A potential role of interleukin 10 in COVID-19 pathogenesis Trends Immunol. 2021 42 3 5 10.1016/j.it.2020.10.012 33214057
Lu, L., Zhang, H., Dauphars, D. J. & He, Y. W. A potential role of interleukin 10 in COVID-19 pathogenesis. Trends Immunol. 42, 3–5 (2021).33214057 10.1016/j.it.2020.10.012
107. Mishra A Chanchal S Ashraf MZ Host-viral interactions revealed among shared transcriptomics signatures of ARDS and thrombosis: a clue into COVID-19 pathogenesis TH Open 2020 4 e403 e412 10.1055/s-0040-1721706 33354650
Mishra, A., Chanchal, S. & Ashraf, M. Z. Host-viral interactions revealed among shared transcriptomics signatures of ARDS and thrombosis: a clue into COVID-19 pathogenesis. TH Open 4, e403–e412 (2020).33354650 10.1055/s-0040-1721706
108. Bai AH Dysregulated lysine acetyltransferase 2b promotes inflammatory bowel disease pathogenesis through transcriptional repression of interleukin-10 J. Crohns Colitis 2016 10 726 734 10.1093/ecco-jcc/jjw020 26802082
Bai, A. H. et al. Dysregulated lysine acetyltransferase 2b promotes inflammatory bowel disease pathogenesis through transcriptional repression of interleukin-10. J. Crohns Colitis 10, 726–734 (2016).26802082 10.1093/ecco-jcc/jjw020
109. Enguita FJ The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response Theranostics 2022 12 3946 3962 10.7150/thno.73268 35664076
Enguita, F. J. et al. The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response. Theranostics 12, 3946–3962 (2022).35664076 10.7150/thno.73268
110. Tayel SI Interplay of LncRNAs NEAT1 and TUG1 in incidence of cytokine storm in appraisal of COVID-19 infection Int. J. Biol. Sci. 2022 18 4901 4913 10.7150/ijbs.72318 35982898
Tayel, S. I. et al. Interplay of LncRNAs NEAT1 and TUG1 in incidence of cytokine storm in appraisal of COVID-19 infection. Int. J. Biol. Sci. 18, 4901–4913 (2022).35982898 10.7150/ijbs.72318
111. Gast M Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients Cardiovasc. Res. 2019 115 1886 1906 10.1093/cvr/cvz085 30924864
Gast, M. et al. Long noncoding RNA NEAT1 modulates immune cell functions and is suppressed in early onset myocardial infarction patients. Cardiovasc. Res. 115, 1886–1906 (2019).30924864 10.1093/cvr/cvz085
112. Wang L Xia JW Ke ZP Zhang BH Blockade of NEAT1 represses inflammation response and lipid uptake via modulating miR-342-3p in human macrophages THP-1 cells J. Cell. Physiol. 2019 234 5319 5326 10.1002/jcp.27340 30259979
Wang, L., Xia, J. W., Ke, Z. P. & Zhang, B. H. Blockade of NEAT1 represses inflammation response and lipid uptake via modulating miR-342-3p in human macrophages THP-1 cells. J. Cell. Physiol. 234, 5319–5326 (2019).30259979 10.1002/jcp.27340
113. Devadoss, D. et al. Distinct mucoinflammatory phenotype and the immunomodulatory long noncoding transcripts associated with SARS-CoV-2 airway infection. Preprint at https://www.medrxiv.org/content/10.1101/2021.05.13.21257152v1 (2021).
114. Firoozi Z Hsa_circ_0000479/Hsa-miR-149-5p/RIG-I, IL-6 axis: a potential novel pathway to regulate immune response against COVID-19 Can. J. Infect. Dis. Med. Microbiol. 2022 2022 2762582 10.1155/2022/2762582 36081604
Firoozi, Z. et al. Hsa_circ_0000479/Hsa-miR-149-5p/RIG-I, IL-6 axis: a potential novel pathway to regulate immune response against COVID-19. Can. J. Infect. Dis. Med. Microbiol. 2022, 2762582 (2022).36081604 10.1155/2022/2762582
115. Lu S RNA-Seq revealed a circular RNA-microRNA-mRNA regulatory network in Hantaan virus infection Front. Cell. Infect. Microbiol. 2020 10 97 10.3389/fcimb.2020.00097 32232013
Lu, S. et al. RNA-Seq revealed a circular RNA-microRNA-mRNA regulatory network in Hantaan virus infection. Front. Cell. Infect. Microbiol. 10, 97 (2020).32232013 10.3389/fcimb.2020.00097
116. Liu F Wu S Ren H Gu J Klotho suppresses RIG-I-mediated senescence-associated inflammation Nat. Cell. Biol. 2011 13 254 262 10.1038/ncb2167 21336305
Liu, F., Wu, S., Ren, H. & Gu, J. Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat. Cell. Biol. 13, 254–262 (2011).21336305 10.1038/ncb2167
117. COVID-19 Multi-omics Blood ATlas (COMBAT) Consortium. A. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity Cell 2022 185 916 938 e958 10.1016/j.cell.2022.01.012 35216673
COVID-19 Multi-omics Blood ATlas (COMBAT) Consortium. A. A blood atlas of COVID-19 defines hallmarks of disease severity and specificity. Cell 185, 916–938 e958 (2022).35216673 10.1016/j.cell.2022.01.012
118. Ingraham NE Understanding the renin-angiotensin-aldosterone-SARS-CoV axis: a comprehensive review Eur. Respir. J. 2020 56 2000912 10.1183/13993003.00912-2020 32341103
Ingraham, N. E. et al. Understanding the renin-angiotensin-aldosterone-SARS-CoV axis: a comprehensive review. Eur. Respir. J. 56, 2000912 (2020).32341103 10.1183/13993003.00912-2020
119. Bonaventura A Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19 Nat. Rev. Immunol. 2021 21 319 329 10.1038/s41577-021-00536-9 33824483
Bonaventura, A. et al. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19. Nat. Rev. Immunol. 21, 319–329 (2021).33824483 10.1038/s41577-021-00536-9
120. Puelles VG Multiorgan and renal tropism of SARS-CoV-2 N. Engl. J. Med. 2020 383 590 592 10.1056/NEJMc2011400 32402155
Puelles, V. G. et al. Multiorgan and renal tropism of SARS-CoV-2. N. Engl. J. Med. 383, 590–592 (2020).32402155 10.1056/NEJMc2011400
121. Xiao F Evidence for gastrointestinal infection of SARS-CoV-2 Gastroenterology 2020 158 1831 1833.e1833 10.1053/j.gastro.2020.02.055 32142773
Xiao, F. et al. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 158, 1831–1833.e1833 (2020).32142773 10.1053/j.gastro.2020.02.055
122. Crook H Long covid-mechanisms, risk factors, and management BMJ 2021 374 n1648 10.1136/bmj.n1648 34312178
Crook, H. et al. Long covid-mechanisms, risk factors, and management. BMJ 374, n1648 (2021).34312178 10.1136/bmj.n1648
123. Xiang M Persistent lung injury and prothrombotic state in long COVID Front. Immunol. 2022 13 862522 10.3389/fimmu.2022.862522 35464473
Xiang, M. et al. Persistent lung injury and prothrombotic state in long COVID. Front. Immunol. 13, 862522 (2022).35464473 10.3389/fimmu.2022.862522
124. Watanabe A One-year follow-up CT findings in COVID-19 patients: a systematic review and meta-analysis Respirology 2022 27 605 616 10.1111/resp.14311 35694728
Watanabe, A. et al. One-year follow-up CT findings in COVID-19 patients: a systematic review and meta-analysis. Respirology 27, 605–616 (2022).35694728 10.1111/resp.14311
125. Swenson KE Swenson ER Pathophysiology of acute respiratory distress syndrome and COVID-19 lung injury Crit. Care Clin. 2021 37 749 776 10.1016/j.ccc.2021.05.003 34548132
Swenson, K. E. & Swenson, E. R. Pathophysiology of acute respiratory distress syndrome and COVID-19 lung injury. Crit. Care Clin. 37, 749–776 (2021).34548132 10.1016/j.ccc.2021.05.003
126. Vishnubalaji R Shaath H Alajez NM Protein coding and long noncoding RNA (lncRNA) transcriptional landscape in SARS-CoV-2 infected bronchial epithelial cells highlight a role for interferon and inflammatory response Genes 2020 11 760 10.3390/genes11070760 32646047
Vishnubalaji, R., Shaath, H. & Alajez, N. M. Protein coding and long noncoding RNA (lncRNA) transcriptional landscape in SARS-CoV-2 infected bronchial epithelial cells highlight a role for interferon and inflammatory response. Genes 11, 760 (2020).32646047 10.3390/genes11070760
127. Wang D Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China J. Am. Med. Assoc. 2020 323 1061 1069 10.1001/jama.2020.1585
Wang, D. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. J. Am. Med. Assoc. 323, 1061–1069 (2020).10.1001/jama.2020.1585
128. Marshall M The lasting misery of coronavirus long-haulers Nature 2020 585 339 341 10.1038/d41586-020-02598-6 32929257
Marshall, M. The lasting misery of coronavirus long-haulers. Nature 585, 339–341 (2020).32929257 10.1038/d41586-020-02598-6
129. Bonow RO Fonarow GC O’Gara PT Yancy CW Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality JAMA Cardiol. 2020 5 751 753 10.1001/jamacardio.2020.1105 32219362
Bonow, R. O., Fonarow, G. C., O’Gara, P. T. & Yancy, C. W. Association of coronavirus disease 2019 (COVID-19) with myocardial injury and mortality. JAMA Cardiol. 5, 751–753 (2020).32219362 10.1001/jamacardio.2020.1105
130. Simoneau CR Ott M Modeling multi-organ infection by SARS-CoV-2 using stem cell technology Cell Stem Cell 2020 27 859 868 10.1016/j.stem.2020.11.012 33275899
Simoneau, C. R. & Ott, M. Modeling multi-organ infection by SARS-CoV-2 using stem cell technology. Cell Stem Cell 27, 859–868 (2020).33275899 10.1016/j.stem.2020.11.012
131. Zheng YY Ma YT Zhang JY Xie X COVID-19 and the cardiovascular system Nat. Rev. Cardiol. 2020 17 259 260 10.1038/s41569-020-0360-5 32139904
Zheng, Y. Y., Ma, Y. T., Zhang, J. Y. & Xie, X. COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. 17, 259–260 (2020).32139904 10.1038/s41569-020-0360-5
132. Helms J Neurologic features in severe SARS-CoV-2 infection N. Engl. J. Med. 2020 382 2268 2270 10.1056/NEJMc2008597 32294339
Helms, J. et al. Neurologic features in severe SARS-CoV-2 infection. N. Engl. J. Med. 382, 2268–2270 (2020).32294339 10.1056/NEJMc2008597
133. Mao L Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China JAMA Neurol. 2020 77 683 690 10.1001/jamaneurol.2020.1127 32275288
Mao, L. et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 77, 683–690 (2020).32275288 10.1001/jamaneurol.2020.1127
134. Monje M Iwasaki A The neurobiology of long COVID Neuron 2022 110 3484 3496 10.1016/j.neuron.2022.10.006 36288726
Monje, M. & Iwasaki, A. The neurobiology of long COVID. Neuron 110, 3484–3496 (2022).36288726 10.1016/j.neuron.2022.10.006
135. Meydan C Madrer N Soreq H The neat dance of COVID-19: NEAT1, DANCR, and co-modulated cholinergic RNAs link to inflammation Front. Immunol. 2020 11 590870 10.3389/fimmu.2020.590870 33163005
Meydan, C., Madrer, N. & Soreq, H. The neat dance of COVID-19: NEAT1, DANCR, and co-modulated cholinergic RNAs link to inflammation. Front. Immunol. 11, 590870 (2020).33163005 10.3389/fimmu.2020.590870
136. Das D Podder S Deregulation of ceRNA networks in frontal cortex and choroid plexus of brain during SARS-CoV-2 infection aggravates neurological manifestations: an insight from bulk and single-cell transcriptomic analyses Adv. Biol. 2022 6 e2101310 10.1002/adbi.202101310
Das, D. & Podder, S. Deregulation of ceRNA networks in frontal cortex and choroid plexus of brain during SARS-CoV-2 infection aggravates neurological manifestations: an insight from bulk and single-cell transcriptomic analyses. Adv. Biol. 6, e2101310 (2022).10.1002/adbi.202101310
137. Ni X Knockdown lncRNA NEAT1 regulates the activation of microglia and reduces AKT signaling and neuronal apoptosis after cerebral ischemic reperfusion Sci. Rep. 2020 10 19658 10.1038/s41598-020-71411-1 33184298
Ni, X. et al. Knockdown lncRNA NEAT1 regulates the activation of microglia and reduces AKT signaling and neuronal apoptosis after cerebral ischemic reperfusion. Sci. Rep. 10, 19658 (2020).33184298 10.1038/s41598-020-71411-1
138. Ni J MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation Brain Behav. Immun. 2015 49 75 85 10.1016/j.bbi.2015.04.014 25934573
Ni, J. et al. MicroRNA let-7c-5p protects against cerebral ischemia injury via mechanisms involving the inhibition of microglia activation. Brain Behav. Immun. 49, 75–85 (2015).25934573 10.1016/j.bbi.2015.04.014
139. Hamming I Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis J. Pathol. 2004 203 631 637 10.1002/path.1570 15141377
Hamming, I. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 203, 631–637 (2004).15141377 10.1002/path.1570
140. Song E Neuroinvasion of SARS-CoV-2 in human and mouse brain J. Exp. Med. 2020 218 e20202135 10.1084/jem.20202135
Song, E. et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. J. Exp. Med. 218, e20202135 (2020).10.1084/jem.20202135
141. Lu L Sleep, exercise, stress, COVID-19, and human health Heart Mind 2022 6 99 100 10.4103/hm.hm_40_22
Lu, L. Sleep, exercise, stress, COVID-19, and human health. Heart Mind 6, 99–100 (2022).10.4103/hm.hm_40_22
142. Meng S Facing sleep and mental health problems in the COVID-19 era: what shall we do? Heart Mind 2022 6 203 206 10.4103/hm.hm_38_22
Meng, S. et al. Facing sleep and mental health problems in the COVID-19 era: what shall we do? Heart Mind 6, 203–206 (2022).10.4103/hm.hm_38_22
143. Zhao Y The phenotype and prediction of long-term physical, mental and cognitive COVID-19 sequelae 20 months after recovery, a community-based cohort study in China Mol. Psychiatry 2023 28 1793 1801 10.1038/s41380-023-01951-1 36690792
Zhao, Y. et al. The phenotype and prediction of long-term physical, mental and cognitive COVID-19 sequelae 20 months after recovery, a community-based cohort study in China. Mol. Psychiatry 28, 1793–1801 (2023).36690792 10.1038/s41380-023-01951-1
144. McWhirter L What is brain fog? J. Neurol. Neurosurg. Psychiatry 2022 94 321 325 10.1136/jnnp-2022-329683 36600580
McWhirter, L. et al. What is brain fog? J. Neurol. Neurosurg. Psychiatry 94, 321–325 (2022).36600580 10.1136/jnnp-2022-329683
145. Asadi-Pooya AA Long COVID syndrome-associated brain fog J. Med. Virol. 2022 94 979 984 10.1002/jmv.27404 34672377
Asadi-Pooya, A. A. et al. Long COVID syndrome-associated brain fog. J. Med. Virol. 94, 979–984 (2022).34672377 10.1002/jmv.27404
146. Loretelli C PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response Jci. Insight 2021 6 e146701 10.1172/jci.insight.146701 34784300
Loretelli, C. et al. PD-1 blockade counteracts post-COVID-19 immune abnormalities and stimulates the anti-SARS-CoV-2 immune response. Jci. Insight 6, e146701 (2021).34784300 10.1172/jci.insight.146701
147. Miyajima M Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior Nat. Immunol. 2017 18 1342 1352 10.1038/ni.3867 29058703
Miyajima, M. et al. Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior. Nat. Immunol. 18, 1342–1352 (2017).29058703 10.1038/ni.3867
148. Rajakulendran S Deletion of chromosome 12q21 affecting KCNC2 and ATXN7L3B in a family with neurodevelopmental delay and ataxia J. Neurol. Neurosurg. Psychiatry 2013 84 1255 1257 10.1136/jnnp-2012-304555 23475819
Rajakulendran, S. et al. Deletion of chromosome 12q21 affecting KCNC2 and ATXN7L3B in a family with neurodevelopmental delay and ataxia. J. Neurol. Neurosurg. Psychiatry 84, 1255–1257 (2013).23475819 10.1136/jnnp-2012-304555
149. Ceban F Fatigue and cognitive impairment in Post-COVID-19 Syndrome: a systematic review and meta-analysis Brain Behav. Immun. 2022 101 93 135 10.1016/j.bbi.2021.12.020 34973396
Ceban, F. et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: a systematic review and meta-analysis. Brain Behav. Immun. 101, 93–135 (2022).34973396 10.1016/j.bbi.2021.12.020
150. Nail LM Winningham ML Fatigue and weakness in cancer patients: the symptoms experience Semin. Oncol. Nurs. 1995 11 272 278 10.1016/S0749-2081(05)80008-7 8578035
Nail, L. M. & Winningham, M. L. Fatigue and weakness in cancer patients: the symptoms experience. Semin. Oncol. Nurs. 11, 272–278 (1995).8578035 10.1016/S0749-2081(05)80008-7
151. Ferrandi PJ Alway SE Mohamed JS The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies J. Appl. Physiol. 2020 129 864 867 10.1152/japplphysiol.00321.2020 32673162
Ferrandi, P. J., Alway, S. E. & Mohamed, J. S. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J. Appl. Physiol. 129, 864–867 (2020).32673162 10.1152/japplphysiol.00321.2020
152. Lv Y Bioinformatics and systems biology approach to identify the pathogenetic link of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome Front. Immunol. 2022 13 952987 10.3389/fimmu.2022.952987 36189286
Lv, Y. et al. Bioinformatics and systems biology approach to identify the pathogenetic link of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Front. Immunol. 13, 952987 (2022).36189286 10.3389/fimmu.2022.952987
153. Ribeiro AF Jr. Muscle satellite cells and impaired late stage regeneration in different murine models for muscular dystrophies Sci. Rep. 2019 9 11842 10.1038/s41598-019-48156-7 31413358
Ribeiro, A. F. Jr. et al. Muscle satellite cells and impaired late stage regeneration in different murine models for muscular dystrophies. Sci. Rep. 9, 11842 (2019).31413358 10.1038/s41598-019-48156-7
154. de Morree A Alternative polyadenylation of Pax3 controls muscle stem cell fate and muscle function Science 2019 366 734 738 10.1126/science.aax1694 31699935
de Morree, A. et al. Alternative polyadenylation of Pax3 controls muscle stem cell fate and muscle function. Science 366, 734–738 (2019).31699935 10.1126/science.aax1694
155. Hirai H MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3 J. Cell. Biol. 2010 191 347 365 10.1083/jcb.201006025 20956382
Hirai, H. et al. MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3. J. Cell. Biol. 191, 347–365 (2010).20956382 10.1083/jcb.201006025
156. Boutet SC Regulation of Pax3 by proteasomal degradation of monoubiquitinated protein in skeletal muscle progenitors Cell 2007 130 349 362 10.1016/j.cell.2007.05.044 17662948
Boutet, S. C. et al. Regulation of Pax3 by proteasomal degradation of monoubiquitinated protein in skeletal muscle progenitors. Cell 130, 349–362 (2007).17662948 10.1016/j.cell.2007.05.044
157. Peeling RW Heymann DL Teo YY Garcia PJ Diagnostics for COVID-19: moving from pandemic response to control Lancet 2022 399 757 768 10.1016/S0140-6736(21)02346-1 34942102
Peeling, R. W., Heymann, D. L., Teo, Y. Y. & Garcia, P. J. Diagnostics for COVID-19: moving from pandemic response to control. Lancet 399, 757–768 (2022).34942102 10.1016/S0140-6736(21)02346-1
158. Clinical management of COVID-19: living guideline, 13 January 2023. (World Health Organization, Geneva, 2023) (WHO/2019-nCoV/clinical/2023.1).
159. Chen B Targeting non-coding RNAs to overcome cancer therapy resistance Signal Transduct. Target. Ther. 2022 7 121 10.1038/s41392-022-00975-3 35418578
Chen, B. et al. Targeting non-coding RNAs to overcome cancer therapy resistance. Signal Transduct. Target. Ther. 7, 121 (2022).35418578 10.1038/s41392-022-00975-3
160. Haroun RA Circulating plasma miR-155 is a potential biomarker for the detection of SARS-CoV-2 infection Pathology 2022 54 104 110 10.1016/j.pathol.2021.09.006 34838331
Haroun, R. A. et al. Circulating plasma miR-155 is a potential biomarker for the detection of SARS-CoV-2 infection. Pathology 54, 104–110 (2022).34838331 10.1016/j.pathol.2021.09.006
161. Taheri M Evaluation of expression of VDR-associated lncRNAs in COVID-19 patients BMC Infect. Dis. 2021 21 588 10.1186/s12879-021-06248-8 34147082
Taheri, M. et al. Evaluation of expression of VDR-associated lncRNAs in COVID-19 patients. BMC Infect. Dis. 21, 588 (2021).34147082 10.1186/s12879-021-06248-8
162. The Novel Coronavirus Pneumonia Emergency Response Epidemiology, T. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) - China, 2020 China CDC Wkly 2020 2 113 122 10.46234/ccdcw2020.032 34594836
The Novel Coronavirus Pneumonia Emergency Response Epidemiology, T. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) - China, 2020. China CDC Wkly 2, 113–122 (2020).34594836 10.46234/ccdcw2020.032
163. Hu H Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination J. Exp. Med. 2016 213 399 414 10.1084/jem.20151426 26903241
Hu, H. et al. Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. J. Exp. Med. 213, 399–414 (2016).26903241 10.1084/jem.20151426
164. Luo Q MicroRNA-486-5p promotes acute lung injury via inducing inflammation and apoptosis by targeting OTUD7B Inflammation 2020 43 975 984 10.1007/s10753-020-01183-3 31940107
Luo, Q. et al. MicroRNA-486-5p promotes acute lung injury via inducing inflammation and apoptosis by targeting OTUD7B. Inflammation 43, 975–984 (2020).31940107 10.1007/s10753-020-01183-3
165. Garcia-Giralt N Circulating microRNA profiling is altered in the acute respiratory distress syndrome related to SARS-CoV-2 infection Sci. Rep. 2022 12 6929 10.1038/s41598-022-10738-3 35484171
Garcia-Giralt, N. et al. Circulating microRNA profiling is altered in the acute respiratory distress syndrome related to SARS-CoV-2 infection. Sci. Rep. 12, 6929 (2022).35484171 10.1038/s41598-022-10738-3
166. Li HB Role of signaling pathway of long non-coding RNA growth arrest-specific transcript 5/microRNA-200c-3p/angiotensin converting enzyme 2 in the apoptosis of human lung epithelial cell A549 in acute respiratory distress syndrome Zhonghua Yi Xue Za Zhi 2018 98 3354 3359 30440128
Li, H. B. et al. Role of signaling pathway of long non-coding RNA growth arrest-specific transcript 5/microRNA-200c-3p/angiotensin converting enzyme 2 in the apoptosis of human lung epithelial cell A549 in acute respiratory distress syndrome. Zhonghua Yi Xue Za Zhi 98, 3354–3359 (2018).30440128
167. Ayeldeen, G. et al. The impact of lncRNA-GAS5/miRNA-200/ACE2 molecular pathway on the severity of COVID-19. Curr. Med. Chem.10.2174/0929867330666230515144133 (2023).
168. Collaborators, C.-E. M. Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020-21 Lancet 2022 399 1513 1536 10.1016/S0140-6736(21)02796-3 35279232
Collaborators, C.-E. M. Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020-21. Lancet 399, 1513–1536 (2022).35279232 10.1016/S0140-6736(21)02796-3
169. Nahand JS The role of miR-146a in viral infection IUBMB Life 2020 72 343 360 10.1002/iub.2222 31889417
Nahand, J. S. et al. The role of miR-146a in viral infection. IUBMB Life 72, 343–360 (2020).31889417 10.1002/iub.2222
170. Frieman M Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane J. Virol. 2007 81 9812 9824 10.1128/JVI.01012-07 17596301
Frieman, M. et al. Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J. Virol. 81, 9812–9824 (2007).17596301 10.1128/JVI.01012-07
171. Yang Y Li L Depleting microRNA-146a-3p attenuates lipopolysaccharide-induced acute lung injury via up-regulating SIRT1 and mediating NF-kappaB pathway J. Drug Target. 2021 29 420 429 10.1080/1061186X.2020.1850738 33185125
Yang, Y. & Li, L. Depleting microRNA-146a-3p attenuates lipopolysaccharide-induced acute lung injury via up-regulating SIRT1 and mediating NF-kappaB pathway. J. Drug Target. 29, 420–429 (2021).33185125 10.1080/1061186X.2020.1850738
172. Jafarinejad-Farsangi S Jazi MM Rostamzadeh F Hadizadeh M High affinity of host human microRNAs to SARS-CoV-2 genome: an in silico analysis Noncoding RNA Res. 2020 5 222 231 10.1016/j.ncrna.2020.11.005 33251388
Jafarinejad-Farsangi, S., Jazi, M. M., Rostamzadeh, F. & Hadizadeh, M. High affinity of host human microRNAs to SARS-CoV-2 genome: an in silico analysis. Noncoding RNA Res. 5, 222–231 (2020).33251388 10.1016/j.ncrna.2020.11.005
173. Cui Y Mir-29a-3p improves acute lung injury by reducing alveolar epithelial cell panoptosis Aging Dis. 2022 13 899 909 10.14336/AD.2021.1023 35656115
Cui, Y. et al. Mir-29a-3p improves acute lung injury by reducing alveolar epithelial cell panoptosis. Aging Dis. 13, 899–909 (2022).35656115 10.14336/AD.2021.1023
174. Li ZH The long noncoding RNA THRIL regulates TNF alpha expression through its interaction with hnRNPL Proc. Natl. Acad. Sci. USA 2014 111 1002 1007 10.1073/pnas.1313768111 24371310
Li, Z. H. et al. The long noncoding RNA THRIL regulates TNF alpha expression through its interaction with hnRNPL. Proc. Natl. Acad. Sci. USA 111, 1002–1007 (2014).24371310 10.1073/pnas.1313768111
175. Zhou HJ Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKbeta/NF-kappaB signaling pathway Am. J. Physiol. Cell Physiol. 2018 315 C52 C61 10.1152/ajpcell.00278.2017 29631367
Zhou, H. J. et al. Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKbeta/NF-kappaB signaling pathway. Am. J. Physiol. Cell Physiol. 315, C52–C61 (2018).29631367 10.1152/ajpcell.00278.2017
176. Keikha R Hashemi-Shahri SM Jebali A The relative expression of miR-31, miR-29, miR-126, and miR-17 and their mRNA targets in the serum of COVID-19 patients with different grades during hospitalization Eur. J. Med. Res. 2021 26 75 10.1186/s40001-021-00544-4 34256840
Keikha, R., Hashemi-Shahri, S. M. & Jebali, A. The relative expression of miR-31, miR-29, miR-126, and miR-17 and their mRNA targets in the serum of COVID-19 patients with different grades during hospitalization. Eur. J. Med. Res. 26, 75 (2021).34256840 10.1186/s40001-021-00544-4
177. Sabbatinelli J Decreased serum levels of the inflammaging marker miR-146a are associated with clinical non-response to tocilizumab in COVID-19 patients Mech. Ageing Dev. 2021 193 111413 10.1016/j.mad.2020.111413 33307107
Sabbatinelli, J. et al. Decreased serum levels of the inflammaging marker miR-146a are associated with clinical non-response to tocilizumab in COVID-19 patients. Mech. Ageing Dev. 193, 111413 (2021).33307107 10.1016/j.mad.2020.111413
178. Onder G Rezza G Brusaferro S Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy J. Am. Med. Assoc. 2020 323 1775 1776
Onder, G., Rezza, G. & Brusaferro, S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. J. Am. Med. Assoc. 323, 1775–1776 (2020).
179. Peckham H Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission Nat. Commun. 2020 11 6317 10.1038/s41467-020-19741-6 33298944
Peckham, H. et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat. Commun. 11, 6317 (2020).33298944 10.1038/s41467-020-19741-6
180. Vai B Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis Lancet Psychiatry 2021 8 797 812 10.1016/S2215-0366(21)00232-7 34274033
Vai, B. et al. Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis. Lancet Psychiatry 8, 797–812 (2021).34274033 10.1016/S2215-0366(21)00232-7
181. Pimenta R MiR-200c-3p expression may be associated with worsening of the clinical course of patients with COVID-19 Mol. Biol. Res. Commun. 2021 10 141 147 34476267
Pimenta, R. et al. MiR-200c-3p expression may be associated with worsening of the clinical course of patients with COVID-19. Mol. Biol. Res. Commun. 10, 141–147 (2021).34476267
182. Liu J Association of sex with clinical outcomes in COVID-19 patients: a retrospective analysis of 1190 cases Respir. Med. 2020 173 106159 10.1016/j.rmed.2020.106159 33010731
Liu, J. et al. Association of sex with clinical outcomes in COVID-19 patients: a retrospective analysis of 1190 cases. Respir. Med. 173, 106159 (2020).33010731 10.1016/j.rmed.2020.106159
183. Xu Y A potentially functional polymorphism in the promoter region of miR-34b/c is associated with an increased risk for primary hepatocellular carcinoma Int. J. Cancer 2011 128 412 417 10.1002/ijc.25342 20309940
Xu, Y. et al. A potentially functional polymorphism in the promoter region of miR-34b/c is associated with an increased risk for primary hepatocellular carcinoma. Int. J. Cancer 128, 412–417 (2011).20309940 10.1002/ijc.25342
184. Gebert LF Miravirsen (SPC3649) can inhibit the biogenesis of miR-122 Nucleic Acids Res. 2014 42 609 621 10.1093/nar/gkt852 24068553
Gebert, L. F. et al. Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. Nucleic Acids Res. 42, 609–621 (2014).24068553 10.1093/nar/gkt852
185. Lu D Thum T RNA-based diagnostic and therapeutic strategies for cardiovascular disease Nat. Rev. Cardiol. 2019 16 661 674 10.1038/s41569-019-0218-x 31186539
Lu, D. & Thum, T. RNA-based diagnostic and therapeutic strategies for cardiovascular disease. Nat. Rev. Cardiol. 16, 661–674 (2019).31186539 10.1038/s41569-019-0218-x
186. Dube U An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations Nat. Neurosci. 2019 22 1903 1912 10.1038/s41593-019-0501-5 31591557
Dube, U. et al. An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. Nat. Neurosci. 22, 1903–1912 (2019).31591557 10.1038/s41593-019-0501-5
187. Akula SM Bolin P Cook PP Cellular miR-150-5p may have a crucial role to play in the biology of SARS-CoV-2 infection by regulating nsp10 gene RNA Biol. 2022 19 1 11 10.1080/15476286.2021.2010959 34904915
Akula, S. M., Bolin, P. & Cook, P. P. Cellular miR-150-5p may have a crucial role to play in the biology of SARS-CoV-2 infection by regulating nsp10 gene. RNA Biol. 19, 1–11 (2022).34904915 10.1080/15476286.2021.2010959
188. Gupta A Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab New Engl. J. Med. 2021 385 1941 1950 10.1056/NEJMoa2107934 34706189
Gupta, A. et al. Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. New Engl. J. Med. 385, 1941–1950 (2021).34706189 10.1056/NEJMoa2107934
189. Weinreich DM REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19 New Engl. J. Med. 2021 384 238 251 10.1056/NEJMoa2035002 33332778
Weinreich, D. M. et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19. New Engl. J. Med. 384, 238–251 (2021).33332778 10.1056/NEJMoa2035002
190. Zhao Y Evaluation of adverse events of bamlanivimab, bamlanivimab/etesevimab used for COVID-19 based on FAERS database Expert Opin. Drug Saf. 2022 22 1 8
Zhao, Y. et al. Evaluation of adverse events of bamlanivimab, bamlanivimab/etesevimab used for COVID-19 based on FAERS database. Expert Opin. Drug Saf. 22, 1–8 (2022).
191. Nhean, S. et al. COVID-19: a review of potential treatments (corticosteroids, remdesivir, tocilizumab, bamlanivimab/etesevimab, and casirivimab/imdevimab) and pharmacological considerations. J. Pharm. Pract. 36, 407–417 (2023).
192. Liu X COVID-19: progress in diagnostics, therapy and vaccination Theranostics 2020 10 7821 7835 10.7150/thno.47987 32685022
Liu, X. et al. COVID-19: progress in diagnostics, therapy and vaccination. Theranostics 10, 7821–7835 (2020).32685022 10.7150/thno.47987
193. Qu L Circular RNA vaccines against SARS-CoV-2 and emerging variants Cell 2022 185 1728 1744.e1716 10.1016/j.cell.2022.03.044 35460644
Qu, L. et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell 185, 1728–1744.e1716 (2022).35460644 10.1016/j.cell.2022.03.044
194. Shah AM Giacca M Small non-coding RNA therapeutics for cardiovascular disease Eur. Heart J. 2022 43 4548 4561 10.1093/eurheartj/ehac463 36106499
Shah, A. M. & Giacca, M. Small non-coding RNA therapeutics for cardiovascular disease. Eur. Heart J. 43, 4548–4561 (2022).36106499 10.1093/eurheartj/ehac463
195. Palihaderu P Therapeutic potential of miRNAs for type 2 diabetes mellitus: an overview Epigenet. Insights 2022 15 25168657221130041 10.1177/25168657221130041 36262691
Palihaderu, P. et al. Therapeutic potential of miRNAs for type 2 diabetes mellitus: an overview. Epigenet. Insights 15, 25168657221130041 (2022).36262691 10.1177/25168657221130041
196. Zhang Q Regulatory roles of microRNAs in insect pests: prospective targets for insect pest control Curr. Opin. Biotechnol. 2021 70 158 166 10.1016/j.copbio.2021.05.002 34090114
Zhang, Q. et al. Regulatory roles of microRNAs in insect pests: prospective targets for insect pest control. Curr. Opin. Biotechnol. 70, 158–166 (2021).34090114 10.1016/j.copbio.2021.05.002
197. Bouchie A First microRNA mimic enters clinic Nat. Biotechnol. 2013 31 577 577 10.1038/nbt0713-577 23839128
Bouchie, A. First microRNA mimic enters clinic. Nat. Biotechnol. 31, 577–577 (2013).23839128 10.1038/nbt0713-577
198. Trujillo RD The potential functions of primary microRNAs in target recognition and repression EMBO J. 2010 29 3272 3285 10.1038/emboj.2010.208 20808284
Trujillo, R. D. et al. The potential functions of primary microRNAs in target recognition and repression. EMBO J. 29, 3272–3285 (2010).20808284 10.1038/emboj.2010.208
199. Dugas JC Dicer1 and miR-219 are required for normal oligodendrocyte differentiation and myelination Neuron 2010 65 597 611 10.1016/j.neuron.2010.01.027 20223197
Dugas, J. C. et al. Dicer1 and miR-219 are required for normal oligodendrocyte differentiation and myelination. Neuron 65, 597–611 (2010).20223197 10.1016/j.neuron.2010.01.027
200. Moyano AL MicroRNA-219 reduces viral load and pathologic changes in theiler’s virus-induced demyelinating disease Mol. Ther. 2018 26 730 743 10.1016/j.ymthe.2018.01.008 29433936
Moyano, A. L. et al. MicroRNA-219 reduces viral load and pathologic changes in theiler’s virus-induced demyelinating disease. Mol. Ther. 26, 730–743 (2018).29433936 10.1016/j.ymthe.2018.01.008
201. Wolter JM Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA Nature 2020 587 281 284 10.1038/s41586-020-2835-2 33087932
Wolter, J. M. et al. Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA. Nature 587, 281–284 (2020).33087932 10.1038/s41586-020-2835-2
202. Phelan JD Staudt LM CRISPR-based technology to silence the expression of IncRNAs Proc. Natl. Acad. Sci. USA 2020 117 8225 8227 10.1073/pnas.2003702117 32245807
Phelan, J. D. & Staudt, L. M. CRISPR-based technology to silence the expression of IncRNAs. Proc. Natl. Acad. Sci. USA 117, 8225–8227 (2020).32245807 10.1073/pnas.2003702117
203. Weng Y Improved nucleic acid therapy with advanced nanoscale biotechnology Mol. Ther. Nucleic Acids 2020 19 581 601 10.1016/j.omtn.2019.12.004 31927331
Weng, Y. et al. Improved nucleic acid therapy with advanced nanoscale biotechnology. Mol. Ther. Nucleic Acids 19, 581–601 (2020).31927331 10.1016/j.omtn.2019.12.004
204. Ning L Development and application of ribonucleic acid therapy strategies against COVID-19 Int. J. Biol. Sci. 2022 18 5070 5085 10.7150/ijbs.72706 35982905
Ning, L. et al. Development and application of ribonucleic acid therapy strategies against COVID-19. Int. J. Biol. Sci. 18, 5070–5085 (2022).35982905 10.7150/ijbs.72706
205. Pfafenrot C Inhibition of SARS-CoV-2 coronavirus proliferation by designer antisense-circRNAs Nucleic Acids Res. 2021 49 12502 12516 10.1093/nar/gkab1096 34850109
Pfafenrot, C. et al. Inhibition of SARS-CoV-2 coronavirus proliferation by designer antisense-circRNAs. Nucleic Acids Res. 49, 12502–12516 (2021).34850109 10.1093/nar/gkab1096
206. Liu CX Chen LL Circular RNAs: characterization, cellular roles, and applications Cell 2022 185 2390 10.1016/j.cell.2022.06.001 35750036
Liu, C. X. & Chen, L. L. Circular RNAs: characterization, cellular roles, and applications. Cell 185, 2390 (2022).35750036 10.1016/j.cell.2022.06.001
207. Trobaugh DW Klimstra WB MicroRNA regulation of RNA virus replication and pathogenesis Trends Mol. Med. 2017 23 80 93 10.1016/j.molmed.2016.11.003 27989642
Trobaugh, D. W. & Klimstra, W. B. MicroRNA regulation of RNA virus replication and pathogenesis. Trends Mol. Med. 23, 80–93 (2017).27989642 10.1016/j.molmed.2016.11.003
208. Vierbuchen T Fitzgerald KA Long non-coding RNAs in antiviral immunity Semin. Cell. Dev. Biol. 2021 111 126 134 10.1016/j.semcdb.2020.06.009 32580911
Vierbuchen, T. & Fitzgerald, K. A. Long non-coding RNAs in antiviral immunity. Semin. Cell. Dev. Biol. 111, 126–134 (2021).32580911 10.1016/j.semcdb.2020.06.009
209. Gao XJ Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression Front. Immunol. 2022 13 980231 10.3389/fimmu.2022.980231 36439162
Gao, X. J. et al. Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression. Front. Immunol. 13, 980231 (2022).36439162 10.3389/fimmu.2022.980231
210. Kumar A COVID-19 mechanisms in the human body-what we know so far Front. Immunol. 2021 12 693938 10.3389/fimmu.2021.693938 34790191
Kumar, A. et al. COVID-19 mechanisms in the human body-what we know so far. Front. Immunol. 12, 693938 (2021).34790191 10.3389/fimmu.2021.693938
211. Shen Q The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection J. Cell. Mol. Med. 2020 24 9472 9477 10.1111/jcmm.15541 32594644
Shen, Q. et al. The ACE2 expression in Sertoli cells and germ cells may cause male reproductive disorder after SARS-CoV-2 infection. J. Cell. Mol. Med. 24, 9472–9477 (2020).32594644 10.1111/jcmm.15541
212. Menni C Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study Lancet 2022 399 1618 1624 10.1016/S0140-6736(22)00327-0 35397851
Menni, C. et al. Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study. Lancet 399, 1618–1624 (2022).35397851 10.1016/S0140-6736(22)00327-0
213. Liu L Mental and neurological disorders and risk of COVID-19 susceptibility, illness severity and mortality: a systematic review, meta-analysis and call for action EClinicalMedicine 2021 40 101111 10.1016/j.eclinm.2021.101111 34514362
Liu, L. et al. Mental and neurological disorders and risk of COVID-19 susceptibility, illness severity and mortality: a systematic review, meta-analysis and call for action. EClinicalMedicine 40, 101111 (2021).34514362 10.1016/j.eclinm.2021.101111
214. Su, S. et al. Epidemiology, clinical presentation, pathophysiology, and management of long COVID: an update. Mol. Psychiatry10.1038/s41380-023-02171-3 (2023).
215. Han Y Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions Transl. Psychiatry 2021 11 499 10.1038/s41398-021-01629-8 34593760
Han, Y. et al. Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions. Transl. Psychiatry 11, 499 (2021).34593760 10.1038/s41398-021-01629-8
216. Schultze JL Aschenbrenner AC COVID-19 and the human innate immune system Cell 2021 184 1671 1692 10.1016/j.cell.2021.02.029 33743212
Schultze, J. L. & Aschenbrenner, A. C. COVID-19 and the human innate immune system. Cell 184, 1671–1692 (2021).33743212 10.1016/j.cell.2021.02.029
217. Abdolahi S Evaluation of miR-200c-3p and miR-421-5p levels during immune responses in the admitted and recovered COVID-19 subjects Infect. Genet. Evol. 2022 98 105207 10.1016/j.meegid.2022.105207 34999004
Abdolahi, S. et al. Evaluation of miR-200c-3p and miR-421-5p levels during immune responses in the admitted and recovered COVID-19 subjects. Infect. Genet. Evol. 98, 105207 (2022).34999004 10.1016/j.meegid.2022.105207
218. Demiray A Serum microRNA signature is capable of predictive and prognostic factor for SARS-COV-2 virulence Turk. J. Biochem. 2021 46 245 253 10.1515/tjb-2020-0520
Demiray, A. et al. Serum microRNA signature is capable of predictive and prognostic factor for SARS-COV-2 virulence. Turk. J. Biochem. 46, 245–253 (2021).10.1515/tjb-2020-0520
219. Fayyad-Kazan M Circulating miRNAs: potential diagnostic role for coronavirus disease 2019 (COVID-19) Infect. Genet. Evol. 2021 94 105020 10.1016/j.meegid.2021.105020 34343725
Fayyad-Kazan, M. et al. Circulating miRNAs: potential diagnostic role for coronavirus disease 2019 (COVID-19). Infect. Genet. Evol. 94, 105020 (2021).34343725 10.1016/j.meegid.2021.105020
220. Gambardella J Role of endothelial miR-24 in COVID-19 cerebrovascular events Crit. Care 2021 25 306 10.1186/s13054-021-03731-1 34433473
Gambardella, J. et al. Role of endothelial miR-24 in COVID-19 cerebrovascular events. Crit. Care 25, 306 (2021).34433473 10.1186/s13054-021-03731-1
221. Grehl C Detection of SARS-CoV-2 derived small RNAs and changes in circulating small RNAs associated with COVID-19 Viruses 2021 13 1593 10.3390/v13081593 34452458
Grehl, C. et al. Detection of SARS-CoV-2 derived small RNAs and changes in circulating small RNAs associated with COVID-19. Viruses 13, 1593 (2021).34452458 10.3390/v13081593
222. Li C Hu X Li L Li JH Differential microRNA expression in the peripheral blood from human patients with COVID-19 J. Clin. Lab. Anal. 2020 34 e23590 10.1002/jcla.23590 32960473
Li, C., Hu, X., Li, L. & Li, J. H. Differential microRNA expression in the peripheral blood from human patients with COVID-19. J. Clin. Lab. Anal. 34, e23590 (2020).32960473 10.1002/jcla.23590
223. Martínez-Fleta P A differential signature of circulating miRNAs and cytokines between COVID-19 and community-acquired pneumonia uncovers novel physiopathological mechanisms of COVID-19 Front. Immunol. 2021 12 815651 10.3389/fimmu.2021.815651 35087533
Martínez-Fleta, P. et al. A differential signature of circulating miRNAs and cytokines between COVID-19 and community-acquired pneumonia uncovers novel physiopathological mechanisms of COVID-19. Front. Immunol. 12, 815651 (2021).35087533 10.3389/fimmu.2021.815651
224. Meidert AS Extracellular vesicle associated miRNAs regulate signaling pathways involved in covid-19 pneumonia and the progression to severe acute respiratory corona virus-2 syndrome Front. Immunol. 2021 12 784028 10.3389/fimmu.2021.784028 34956213
Meidert, A. S. et al. Extracellular vesicle associated miRNAs regulate signaling pathways involved in covid-19 pneumonia and the progression to severe acute respiratory corona virus-2 syndrome. Front. Immunol. 12, 784028 (2021).34956213 10.3389/fimmu.2021.784028
225. Srivastava S Evaluation of altered miRNA expression pattern to predict COVID-19 severity Heliyon 2023 9 e13388 10.1016/j.heliyon.2023.e13388 36743852
Srivastava, S. et al. Evaluation of altered miRNA expression pattern to predict COVID-19 severity. Heliyon 9, e13388 (2023).36743852 10.1016/j.heliyon.2023.e13388
226. Wang Y Plasma cell-free RNA characteristics in COVID-19 patients Genome Res. 2022 32 228 241 10.1101/gr.276175.121 35064006
Wang, Y. et al. Plasma cell-free RNA characteristics in COVID-19 patients. Genome Res. 32, 228–241 (2022).35064006 10.1101/gr.276175.121
227. Yang P Downregulated miR-451a as a feature of the plasma cfRNA landscape reveals regulatory networks of IL-6/IL-6R-associated cytokine storms in COVID-19 patients Cell. Mol. Immunol. 2021 18 1064 1066 10.1038/s41423-021-00652-5 33637960
Yang, P. et al. Downregulated miR-451a as a feature of the plasma cfRNA landscape reveals regulatory networks of IL-6/IL-6R-associated cytokine storms in COVID-19 patients. Cell. Mol. Immunol. 18, 1064–1066 (2021).33637960 10.1038/s41423-021-00652-5
228. Zhang Y Comparative analysis of long non-coding RNA expression and immune response in mild and severe COVID-19 Front. Mol. Biosci. 2022 9 835590 10.3389/fmolb.2022.835590 35573725
Zhang, Y. et al. Comparative analysis of long non-coding RNA expression and immune response in mild and severe COVID-19. Front. Mol. Biosci. 9, 835590 (2022).35573725 10.3389/fmolb.2022.835590
