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Plant Signal Behav
Plant Signal Behav
Plant Signaling & Behavior
1559-2316
1559-2324
Taylor & Francis

39312190
10.1080/15592324.2024.2382497
2382497
Version of Record
Review Article
Review
Advances in understanding the interaction between Solanaceae NLR resistance proteins and the viral effector Avr
J. WEI ET AL.
Plant Signaling & Behavior
Wei Jianming a
Li Yunzhou a
Chen Xiangru a
Tan Ping b
Muhammad Tayeb c
Liang Yan d
a College of Agriculture, Guizhou University , Guiyang, China
b Field management station, Guiyang Agricultural Test Center , Guiyang, China
c Key Laboratory of Genome Research and Genetic Improvement of Xinjiang Characteristic Fruits and Vegetables, Institute of Horticulture Crops, Xinjiang Academy of Agricultural Sciences , Urumqi, China
d College of Horticulture, Northwest A&F University , Yangling, China
CONTACT Yunzhou Li yzli1@gzu.edu.cn College of Agriculture, Guizhou University, Guiyang 550025, China
Yan Liang Liangyan@nwsuaf.edu.cn College of Horticulture, Northwest A&F University, Yangling 712100, China
23 9 2024
2024
23 9 2024
19 1 2382497Integra23 9 2024
Integra23 9 2024
12 5 2024
10 7 2024
12 7 2024
© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

ABSTRACT

The rising prevalence of viral-induced diseases, particularly those caused by certain strains, poses a substantial risk to the genetic diversity of Solanaceae crops and the overall safety of horticultural produce. According to the “gene-for-gene” hypothesis, resistance proteins are capable of selectively identifying nontoxic effectors produced by pathogens, as they are under purview of the host’s immune defenses. The sensitivity and responsiveness of Solanaceae plants to viral attacks play a crucial role in shaping the outcomes of their interactions with viruses. Pathogenic organisms, devise an array of infection tactics aimed at circumventing or neutralizing the host’s immune defenses to facilitate effective invasion. The invasion often accomplishes by suppressing or disrupting the host’s defensive mechanisms or immune signals, which are integral to the infection strategies of such invading pathogens. This comprehensive review delves into the myriad approaches that pathogenic viruses employ to infiltrate and overcome the sophisticated immune system of tomatoes. Furthermore, the review explores the possibility of utilizing these viral strategies to bolster the resilience of horticultural crops, presenting a hopeful direction for forthcoming progress in plant health and agricultural stability.

KEYWORDS

Solanaceae crops
resistance protein NLR
effector Avr
host interaction
antiviral
Guizhou Provincial Basic Research Program National Science Foundation of China 10.13039/501100001809 Grant No. 32060679 Guizhou University 10.13039/501100003459 No. Gui Da Pei Yu [2019]52 Guiyang Science and Technology Bureau’s 2021 Science and Technology Innovation Project Zhuke Project [2022] No. 3 This work was funded by the Guizhou Provincial Basic Research Program (Natural Science) (Qian Ke Ji Chu-ZK [2024] Zhong Dian 013; Qian Ke Ji Chu-ZK [2022] YiBan 071), the National Science Foundation of China [Grant No. 32060679], Guizhou University [No. Gui Da Pei Yu [2019]52] and the Guiyang Science and Technology Bureau’s 2021 Science and Technology Innovation Project [Zhuke Project [2022] No. 3].
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pmcIntroduction

The disruption of food supplies caused by plant diseases can have a destabilizing effect on food security. Crops are continually threatened by various pathogens such as viruses, fungi, bacteria, and nematodes that can cause damage to agriculture crops. Similarly, horticultural crops are subject to a multitude of pathogenic threats, throughout their growth stages.1–3 Plant viruses are a major constraint to agriculture, accounting for nearly 50% of newly emerging plant diseases and causing an estimated economic loss greater than $30 billion annually.4 Presently, there is no known method for the complete elimination of viruses. Thus, when crops become infected, the infected plants must be completely eradicated to avoid further spread. The emergence of the tomato brown rugose fruit virus (ToBRFV) in major tomato growing regions led to a significant decrease in crop yield, with reductions of up to 16% and, in severe cases, complete crop failure observed.5 The increasing impact of global climate changes adds further intricacies to the development of plant diseases. Furthermore, the occurrence of multiple viral outbreaks worldwide poses significant challenges to ensuring crop safety.6 Plant viruses are mainly transmitted by vector insects, including the aphids (Aphidoidea), whitefly (Bemisia tabaci), and thrips (Frankliniella occidentalis), which serve as carriers for their spread.7 Upon invasion of host plants, most viruses first undergo a decoating process, releasing nucleic acid substances such as RNA or DNA, and then rapidly replicate, transcribe, translate, and assemble themselves by hijacking and exploiting host-related proteins, completing their invasion cycle.8,9 Mature viral particles or viral ribonucleoprotein complexes are transported through the plant’s vascular system to various tissues and organs, with the exception of apical meristems.10 Certain plants infected with viruses exhibit observable local or systemic symptoms, including leaf yellowing, curling, deformities, stunted growth, or diminished yield.11

Effectors are molecules produced by pathogens, including proteins, peptides, or other small molecules, that play a role in modulating the host’s cellular processes to facilitate infection. Effectors are secreted by the pathogen and can suppress the host’s immune response, acquire nutrients, or manipulate host cell functions to the pathogen’s advantage. They are often specific to the pathogen species and can be highly variable.12

Avirulence factors (Avr) are a subset of effectors that are recognized by the host plant’s immune system. When a plant has a specific resistance gene (R gene) that encodes an NLR (Nucleotide-binding Leucine-rich repeat) receptor, it can directly or indirectly recognize an Avr factor. This recognition triggers a strong immune response known as the hypersensitive response (HR), which can limit pathogen growth and spread.13

The key difference between effectors and Avr factors is their role in the interaction with the host plant. Effectors are generally secreted to promote infection and can include a wide range of molecules that manipulate host defenses or cellular processes. Avr factors are specific types of effectors that are recognized by the host’s R genes and trigger a defense response.14

In a sense, an Avr factor is an “exposed” effector because it is recognized by the host’s immune system. However, not all effectors are Avr factors, and not all Avr factors are necessarily recognized by NLRs; some may be recognized by other types of immune receptors.15

Avirulence factors (Avr) play a pivotal role in the process of infection by horticultural crop pathogens. Avr can modulate plant immune responses through various mechanisms, including direct or indirect interactions with host resistance proteins such as NLRs. However, it is important to note that not all viral effectors engage with NLRs, and the plant’s defense mechanisms are diverse and multi-layered. However, within specific plant hosts or cultivars, virus-derived proteins may function as pivotal elements impacting plant defenses reactions. In some cases, they elicit extreme resistance (ER) as regulatory agents within the host. The zig-zag paradigm of plant-pathogen interplay, allows for the categorization of plant innate immunity into two distinct layers: pathogen-associated molecular patterns (PAMPs) initiate a state of immunity referred to as PTI (PAMP-triggered immunity), whereas effector-triggered immunity (ETI) is considered a reaction to effectors.16 PTI is initiated through the specific sensing of bacterial flagellin, fungal chitin, and other pathogen-derived molecular patterns (PAMPs) by plant cell membrane-anchored receptors known as pattern recognition receptors (PRRs). Recognition of these PAMPs by plants triggers a robust resistance response, functioning as the primary barrier against pathogens. Previously, plant antiviral immunity was disregarded in the conventional PTI model. Nevertheless, recent investigations have demonstrated the involvement of PTI in plant immunity against viral pathogens. For instance, (I) emerging concepts in antiviral immunity include the recognition of double-stranded RNA (dsRNA) and viral nucleic acids as PAMPs.17–20 (II) the influence of plant viruses on cell wall remodeling indicates that viral infections may modulate pathways analogous to damage-associated molecular patterns (DAMPs), resembling PTI, and involving similar molecular mechanisms.21,22 (III) the involvement of multiple PRRs, such as NIK1, BAK1, BIR1, BKK1 (BAK1-like 1), Serk1 and MAPKs, during antiviral PTI.23–25 and (IV) engagements between viral-originated proteins and constituents of the host’s intrinsic immune response pathway, disrupt PTI-mediated signal transduction and induce effector-triggered susceptibility (ETS).26–29

Furthermore, to withstand environmental stress, plants have evolved a class of resistance proteins known as NLRs (nucleotide-binding domains and leucine-rich repeats). These proteins can directly or indirectly recognize pathogen effectors (proteins, peptides, or other small molecules) or avirulence factors (Avr) and activate effector-triggered immunity (ETI), thereby initiating the second line of defense.16 ETI is frequently indicated by a hypersensitive response (HR), which is characterized by swift cell mortality, the initiation of reactive oxygen species (ROS) and salicylic acid (SA), and the induction of gene expression linked to defense mechanisms.30 The discovery of Avr effectors and NLR proteins involved in different virus – plant interactions date back to 1984.31 The majority of NLR proteins possess a nucleotide-binding domain and leucine-rich repeat domain (NB-LRR), frequently accompanied by an N-terminal coiled-coil domain (CC) or a Toll/interleukin-1 receptor (TIR) domain. An increasing body of evidence substantiates the concept that plants utilize established ETI mechanisms to control viral infections. Despite the continued efforts to develop novel resistant cultivars, pathogens have exhibited remarkable resilience and adaptability, enabling them to adapt and overcome the disease resistance mechanisms of the host when confronted with the presence of resistant varieties. Consequently, the development of innovative strategies to enhance plant resistance against pathogens is of paramount importance for the assurance of global food security. This review offers a thorough examination of the recent advances in the comprehension of the involvement of Avr and horticulture crop host resistance proteins (NLRs) in plant immunity.

NLR protein structure

NLR proteins and their importance

NLR proteins, encoded by R genes, are a key component of the plant immune system. They are present in many plant species and are crucial for triggering defense responses against pathogen invasion. These proteins are widely present in many plant species and are crucial for the plant immune system. For example, tomato and potato contain approximately 394 and 755 R genes, respectively.32

Nucleotide-binding site (NBS) domain

The nucleotide-binding site (NBS) domain represents a critical structural element within R proteins and encompasses various subdomains, including the P-loop, kinase-2, and kinase-3a subdomains. These subdomains are responsible for binding to ATP or GTP and forming protein aggregates through interactions between NBS domains. The NBS domain is frequently associated with a leucine-rich repeat-containing protein (LRR) domain and is characterized by the presence of numerous repetitive sequences rich in leucine.

Nucleotide-binding site (NBS)

When pathogens interfere with the immune response of the host plant through the release of effectors, the LRR domain recognizes the effectors encoded by the pathogen, initiates the defenses response and triggers a series of immune responses to resist pathogen invasion. The LRR domain is typically situated at the C-terminus of the NBS domain and exhibits considerable diversity in length and organization. This diversity enables different NLR proteins to recognize distinct effectors, thereby triggering specific immune responses.

N-terminal domains

Some NLRs have N-terminal domains, such as TIR (Toll/interleukin-1 receptor) or CC (coiled-coil) domains. These domains are involved in downstream signaling pathways and transcriptional regulation of defense responses. For instance, in Arabidopsis, RPW8 is an NLR protein that is solely composed of a CC domain, which confers broad-spectrum resistance against powdery mildew. CC domains related to RPW8 are commonly known as CCRs. Consequently, based on their distinct N-terminal domains, plant NLRs can be classified into three primary classes: TNL, CNL, and RNL. These domains play crucial roles in downstream signaling pathways and the transcriptional regulation of defenses responses.33–35 In addition to the aforementioned two classes of R proteins, there are other classes of receptor-like proteins (RLPs). However, the majority of R gene products (NLR proteins) engaged in virus-Avr interactions primarily fall into the CC-NLR (NBS-LRR, NLR) class, exemplified by Rx-1, Sw-5, Tm-2, and the TIR-NLR class, represented by N and Rsv1.36

Classification of NLR proteins

Based on their N-terminal domains, NLRs are classified into three primary classes: TNL (TIR-NLR), CNL (CC-NLR), and RNL (no recognizable N-terminal domain).37

NB-ARC domain

The NB-ARC domain is part of the STAND superfamily and functions as a molecular switch in various biological processes, including immune regulation. It interacts with nucleotides (ADP/ATP), leading to conformational changes in NLR proteins, which are then activated to transmit signals and initiate the immune response.38 The NB-ARC (nucleotide-binding adaptor shared by Apaf-1, R proteins, and Ced-4) domain is a protein domain composed of three subdomains: the nucleotide-binding (NB) site, which is shared with apoptotic protease activating factor-1 (Apaf-1), resistance proteins (R proteins), and the cell death protein Ced-4. The NB-ARC protein family is classified within the signal transduction ATPases with numerous domains (STAND) superfamily, which represents a subfamily that encompasses multiple domains. This protein group functions as a molecular switch involved in diverse biological processes, including immune system regulation, cell apoptosis, and transcriptional control. The interaction of the NB-ARC domain with different nucleotides (ADP/ATP) leads to distinct states of NLR proteins. It is generally accepted that NLR proteins bound to ADP are in a closed or inactive state, whereas binding to ATP induces a conformational change, during which the NLR protein is considered to be in an open or active state. Furthermore, the NB-ARC domain typically includes Walker A (P-loop), RNBS-A, and Walker B motifs, which are responsible for ATP binding and hydrolysis. Once activated, NLRs transmit signals and initiate the plant’s immune system.39

Role in plant immunity

The TIR/CC, NB-ARC, and C-terminal LRR domains serve as receptors for detecting pathogenic invasion. NLR proteins can perceive pathogenic effectors, triggering immune responses that may lead to HR and programmed cell death (PCD) at the infection site. In addition to the C-terminal LRR domain, which is rich in LRRs, noncanonical integrated domains play a crucial role in the specific recognition of effectors in plants. The structure of NLR proteins is highly conserved, and understanding their structure and function is essential for cultivating disease-resistant horticultural crops. In recent years, notable advancements have been made in the identification of R genes in diverse plant species, including tomato. These findings have broadened our understanding of plant immune mechanisms and revealed novel avenues for developing more effective strategies in the field of plant disease management.

Activation of NLR proteins

The activation status of NLR proteins is contingent upon the presence of pathogen avr factors.40 In the absence of pathogens, NLRs typically remain in a self-inhibited state. Three-dimensional structural analysis revealed the inhibitory role of the C-terminal LRR domain, which encloses the NB-ARC and CC/TIR-NB-LRR domains, impedes nucleotide exchange and restricts the self-activation of NLR proteins to a certain degree. For instance, during the process of recognizing the R×1 protein from the potato virus X (PVX) coat protein (CP), the CC-LRR domain of R×1 interacts with CP, inducing a conformational alteration between the N-terminal domain (NTD) of the LRR domain and the ARC2 domain. This conformational change subsequently triggers the activation of the disease resistance response. During this conformational change, the nucleotide-binding site of the NB domain becomes exposed, enabling the exchange of ATP-ADP. A comprehensive investigation revealed the regulatory mechanism underlying the autoinhibition and activation of NBS-LRR during Tomato spotted wilt virus (TSWV) infection, which involves a cascade of processes. Chen et al.. (2016) demonstrated that the leucine-rich repeat (LRR) domain of the Sw-5b resistance protein acts to impede the central nucleotide-binding adaptor shared by the Apaf-1, R proteins, and Ced-4 (NB-ARC) domain, thereby maintaining self-inhibition of the NB-LRR region.41

In response to TSWV infection, the NB-LRR segment of the Sw-5b resistance protein undergoes specific activation, subsequently initiating a hypersensitive response. This suggests that during pathogen invasion, the NB-LRR segment of Sw-5b is released from self-inhibition and transitions into an activated state. Furthermore, the study revealed that the coiled-coil (CC) domain of Sw-5b inhibits the self-activation of NB-LRR, while an additional N-terminal Solanaceae domain (NTD) acts as a positive regulator to fully activate the resistance protein. This additional NTD may alleviate the inhibitory effect of the CC domain, promoting the complete activation of the resistance protein.41 Previously it was found that the N-terminal Solanaceae domain (SD) of the Sw-5b resistance protein restricted the replication and movement of TSWV in the cytoplasm and nucleus. Further, the research also revealed interactions between SDs and input proteins. Silencing the expression of the α and β input proteins disrupted the nuclear transport of Sw-5b and interfered with the host’s immune defenses mechanism against systemic TSWV infection.42 Similarly, it was demonstrated that NSs facilitate the interaction between COI1, TIR1, or MAX2 and TCP21, thereby impeding the deterioration of the relevant transcriptional inhibitors.43 In the absence of Avr protein, the corresponding NLR protein may not be activated, and downstream defenses response genes may not be expressed, resulting in a weak or no defenses response and susceptibility to viral infection. Therefore, the presence of NLR and Avr is essential for gene-for-gene resistance in tomato plants.44 In the absence of the Avr protein, the defense response is inhibited, and plants may not be able to resist the virus. Table 1 provides a summary of the resistance genes (R) present in tomatoes and their corresponding virus-encoded Avr genes.Table 1. Avr factors of plant viruses and their corresponding NLR resistance genes.

Virus	Source	NLR	Avr	Type	References	
Tobacco mosaic virus, TMV	Nicotiana glutinosa	N	p50	TIR-NLR	45,46	
Tomato mosaic virus, ToMV	Solanum hirsutum	Tm1	RP	CC-NLR	46–49	
Solanum peruvianum	Tm2	MP	CC-NLR	47–49	
Tm22	
Tomato spotted wilt virus, TSWV	Solanum lycopersicum	Sw5b	NSm	SD-CC-NLR	48–51	
Nicotiana alata	RTSW	NSm	Not reported	52	
Capsicum chinense	Tsw	NSs	CC-NLR	53	
Solanum lycopersicum	Sl5R–1	SlTGA9	CC-NLR	54	
Tomato leaf curl virus, ToLCV	Solanum pimpinellifolium	AAU2019	unknown	unknown	55	
Tomato yellow leaf curl virus, TYLCV	Solanum habrochaites	Ty-2	Rep/C1	Not reported	56,57	
Solanum chilense	Ty-1, Ty-3	RdRP	CC-NLR	58	
Solanum chilense	Ty-4	unknown	Not reported	59	
Tomato cultivar Tyking or S. peruvianum	Ty-5	Pelota	CC-NLR	60–63	
Solanum chilense	Ty-6	unknown	unknown	64	
Solanum lycopersicum	CP	MAPKKK	unknown	65	
Tomato leaf curl New Delhi virus, ToLCNDV	Solanum lycopersicum	Sw5a	ARC4	SD-CC-NLR	66	
Beet black scorch virus, BBSV	Solanum lycopersicum	CP	MAPKK	unknown	67	
Tomato yellow leaf curl China virus, TYLCCNV	Solanum lycopersicum	βC1	MKK2, MKK4	unknown	26	
Tomato chlorosis virus, ToCV	Solanum peruvianum	Tm-22, Tm-2	MP	CC-NLR	49	
N. benthamiana	SCFTIR1	p22	CC-NLR	68	
Tomato bushy stunt virus, TBSV	N. benthamiana	P19	S07B1, M14B2	RNAi	69	
Tomato brown rugose fruit virus, ToBRFV	Solanum lycopersicum	Tm2, Tm-22	MP	CC-NLR	70	
Cucumber mosaic virus, CMV	Arabidopsis thaliana	RCY1	CP	CC-NLR	71	
Phaseolus vulgaris cv. Othello	RT4–4	2a	TIR-NLR	72	
Potato virus X, PVX	Solanum tuberosum	Rpi-vnt1.1	NLRs	TIR-NLR	63	
Nicotiana benthamiana	Rx1	CP	CC-NLR	64	
Solanum tuberosum	Rx2	CP	CC-NLR	73	
Nx	CP	unknown	74	
Nb	MP	unknown	75	
Potato virus Y, PVY	Capsicum annuum	Pvr4	NIb	CC-NLR	76	
Solanum stoloniferum	Rysto	NIaPro or CP?	TIR-NLR	77,78	
Pepper mild mottle virus, PMMoV	Capsicum annuum	L1–4	CP	CC-NLR	79	
Abbreviations: RP, replication protein; MP, movement protein; CP, coat protein; NSm, cell–cell movement protein; NSs, silencing suppressor; NIB, RNA-dependent RNA polymerase. SD-CC, Solanaceae domain–coiled-coil domain.

Regulation of plant immune signaling

Immune receptors are capable of detecting microbial infections, which then trigger a series of interconnected and ever-changing signaling pathways.80 It is therefore essential to ensure a high degree of regulation of this network in order to initiate an effective immune response.81 Microbial pathogens have developed ways to disrupt the reliable functioning of host signaling regulatory networks as a result of this disruption.16 Upon recognition of the Avr effector by the NLR protein, plant immune responses are initiated.82 These reactions involve the initiation of defenses-related signal transduction routes and the adjustment of genetic material manifestations, including those involved in plant hormone synthesis, cell wall reinforcement, and the expression of defenses-related genes.83 The activation of these downstream genes rapidly initiates an effective defenses response, limiting the spread of the virus within plant cells.84 The NLR and viral Avr proteins are pivotal elements in plant resistance to viral infections. During viral infection, the Avr gene of the pathogen is expressed, leading to the production of nontoxic Avr proteins. These nontoxic Avr proteins do not inherently produce toxic effects on the plant. Instead, their role is to be recognized by the plant’s immune system.85 These nontoxic Avr proteins can be identified by plant NLR proteins.86 NLR proteins interact with nontoxic Avr proteins, triggering defense responses that are similar to those induced when Avr proteins are recognized during viral infection.87 This response enables plants to activate defense mechanisms before actual viral infection occurs. The recognition and interaction of nontoxic Avr proteins by NLR proteins initiates the activation of defenses-related signal transduction pathways. This activation triggers a cascade of defenses responses, including the synthesis of antipathogenic compounds and the initiation of cell death programs. Therefore, when plants are exposed to viral infection, the defenses system is preemptively activated, allowing for faster and more efficient recognition and resistance against viral invasion.88

The mechanism of viral effector perception by NLR resistance genes

Some viruses can be transmitted through vector insects. If the virus has not yet entered tomato plant cells, the plant can prevent vector transmission by using its own trichomes and volatile substances to prevent the virus from entering the host.89 Plant viruses can be classified into two categories; high pathogenic viruses and weak pathogenic viruses. Highly pathogenic viruses can rapidly lead to plant death, while weakly pathogenic viruses can reproduce and allowing the host to continue growing.6 Upon entering host cells, viral particles undergo cleavage of their glycoproteins with host tissues, leading to fusion with lysosomal membranes and release of the virus’s genetic material (DNA or RNA) into the host cell cytoplasm for replication.90 Additionally, the virus can exploit host cytoplasmic ribosomes to produce new proteins (CPs or MPs) using viral nucleic acids, thereby generating new viral particles. Owing to their inherently parasitic nature, most plant viruses exhibit low pathogenicity.91 Once the virus has gained entry into the host cell, it has the potential to engage in long-distance movement through the phloem and short-range transfer facilitated by plasmodesmata.30 The currently identified tomato virus resistance genes include Tm-1, Tm-2, Tm-22, Sw5a, and Sw5b, which interact with the corresponding virus target proteins (Avr), NLR proteins, RP proteins, MP proteins, CP proteins, and AC4 proteins. This interaction triggers the HR and thus limits the systemic invasion of the virus. Figure 1 provides a summary of the mechanisms of tomato resistance to viruses. Figure 1. Interaction between the virus-infected tomato host resistance protein NLR and the viral effector (avr). a: LRR domain, b: NBS domain, c: CC/TIR domain; CP: coat protein; MP: movement protein; PR: polymerase; RdRp: RNA-dependent RNA polymerase; SGT1 and RanGAP2: proteins.

NLR-triggered antiviral responses can act directly or indirectly. Avr can directly interact with the NLR or activate resistance responses by mediating the interaction between the effector Avr and NLR.30 However, the effector recognition sites of NLR proteins are not conserved but rather specific to each virus. For example, the replicated protein (Rep) of tobacco mosaic virus (TMV) interacts with the TIR-NLR domain of the N gene,46 and the coat protein (CP) of PVX can recognize the LRR-Rx domain.92 Zhu et al. (2017) reported the detection of immunity to the emerging TSWV by identifying a conserved 21-amino acid peptide segment within the viral movement protein NSm (designated NSm21).93 Moreover, the recognition of NSm21 by Sw-5b might conceivably perturb intramolecular associations between the LRR and NB-ARC domains, potentially influencing the recognition of the R927 residue and transforming NSm21 recognition into Sw-5b activation.93 The NTD that interacts with LRR was identified as a key player in the activation of NLR receptors. This interaction enables the recognition of the movement protein NSm in TSWV and enhances the detection capability of low-level effectors.94 A comprehensive investigation of the Sw-5b resistance gene revealed that the Sw-5b immune receptor protein possesses the capacity to impede viral replication, intercellular mobility, and long-range transport. The Sw-5b protein initiates a coordinated immune response within the cytoplasm and nucleus, effectively enhancing resistance against viral invasion.42 The aforementioned studies demonstrated that Sw-5b, when localized in the cytoplasm, robustly induces programmed cell death, effectively impeding the spread of TSWV within cellular tissues. However, it is unable to impede virus transport between cells or within vascular bundles. Conversely, Sw-5b, which is situated within the cell nucleus, enhances the suppression of the intracellular cell-to-cell movement and intercellular vascular bundle transport of TSWV, even if it performs poorly at suppressing viral reproduction.42 Moreover, Sw-5b in the cytoplasm and nucleus can function synergistically, but with different effects at different stages of viral infection.

Eradication of immune signaling components

Upon entering the cell, the virus first triggers the MAPK cascade signaling system or G protein phospholipase C (PLC) to initiate the Ca2+ signaling pathway, regulating the downstream gene transcription factors WRKY1 and WRKY3 or disease resistance genes.95,96 The microbial effector repertoire plays a vital role in evading plant PTIs. A multitude of effectors from a diverse array of microbial pathogens have been identified as targeting key signaling components, including BAK1 and MAPKs. BAK1 is essential for signaling initiated by multiple MAMPs and serves as a coreceptor for an array of PRRs. Viruses employ a range of distinct effectors to target MAPKs, and their coat proteins either directly or indirectly interact with MAPKKK or MAPKK, respectively. The βC1 protein, which is encoded by the β-satellite of tomato yellow curl leaves, impedes host immunity by preventing MAPKK2 and MAPK4 activation in N. benthamiana.26 The transporter phosphatidylethanolamine binding protein 4 (PEBP4) of Bemisia tabaci and the Raf1 effector protein compete for the coat protein (CP) of tomato yellow leaf curl virus (TYLCV), resulting in the termination of MAPK signaling components by hindering phosphorylation, which in turn activates programmed cell death.65 In their study, Gao et al. (2022) investigated the interaction between the beet black scorch virus (BBSV) CP and mitogen-activated protein kinase kinase kinase α (MAPKKKα).67 Their findings revealed that CP does not have a direct impact on MAPKKKα, but rather competes with it in a dose-dependent manner to disrupt the interaction between 14-3-3α and MAPKKKα (Figure 2). This competitive interference leads to the destabilization of MAPKKKα and the disruption of its function in mediating antiviral defenses.97 NRC hNLRs, which are partially redundant central regulators of CNL signaling in Solanaceae plants, can confer resistance to various plant pathogens, including viruses, bacteria, oomycetes, nematodes, and insects.44,98 The tomato Prf-mediated immunity is dependent on NRC2 and NRC3, while NRC4 is responsible for regulating potato Rpi-blb2-mediated resistance. Furthermore, various CNLs, such as Sw5b, Rx, Bs2, and R8, which originate from different Solanaceae plants, are redundantly regulated by these three NRCs. The functional redundancy of hNLRs contributes to the complexity and resilience of plant immune system. However, pathogens, which are microorganisms, release effectors that target and disable these NRC nodes. For instance, the immunity of Sw-5b to TSWV was weakened by suppressing NRC2/3/4.99 The hypothesis was put forth that the resistance of Solanaceae to PVX under high temperatures is likely the result of the sensor NLR, rather than its downstream signaling components.100 AVRcap1b, an effector of P. infestans, and SS15, an effector of the cyst nematode, both target NRC2 and NRC3, thus preventing the activation of NLRs that are signaled through these two NRCs.101 Two RXLR effectors of Phytophthora infestans, PexRD2 and Pi17316, have been identified as interacting with MAPK kinase kinases to facilitate infection of N. benthamiana and S. tuberosum, respectively. Figure 2. Regulation of plant immune signaling. Solid arrows represent established signal transduction pathways, while dashed arrows indicate relationships derived from genetic studies. 12OH-JA, 12-hydroxyjasmonic acid; JA-Ile, jasmonic acid-isoleucine; JAZ, jasmonate ZIM domain protein; MAMP, microbe-associated molecular pattern; MAPKK, MAPK kinase; MAPKKK, MAPK kinase kinase.

Rewiring of host hormone signaling

Plant-synthesized metabolites play a crucial role in the transduction defenses signal. The primary signaling molecules that regulate plant defenses against various microbial diseases include SA, jasmonic acid (JA), and ethylene (ET).102,103 SA participates in the mechanism of protection against biotrophic infections in dicotyledonous plants, whereas ethylene and jasmonate are often linked to defenses against necrotrophic diseases.104 A complex regulatory network that supports plant immunity is created by the interactions between these signals and other signaling pathways. Increasing evidence demonstrates that microbial infections can evade the defense mechanisms of hosts through manipulation of plant hormone synthesis and communication networks, as illustrated by coronatine.105 Infection with begomoviruses has been shown to decrease the levels of jasmonic acid (JA), resulting from inhibited JA biosynthesis/catabolism or signaling pathways. This reduction facilitates enhanced performance by whitefly vectors.106–108 Infection of tobacco plants with tomato yellow leaf curl China virus (TYLCCNV) has been shown to enhance the efficiency of the whitefly vector.109 The βC1 protein, a viral satellite, is responsible for this enhanced performance, as it inhibits JA biosynthesis/catabolism, JA signaling, and terpenoid biosynthesis/catabolism.106,107 Similarly, infection by tomato yellow leaf curl virus (TYLCV) impairs JA signaling in tomato plants, leading to the suppression of plant defenses and, in turn, enhanced performance of whitefly vector.110 Recent research on TYLCV and tobacco demonstrated that the viral C2 protein is capable of blocking JA signaling via a distinct mechanism. Experimental evidences from both in vivo and in vitro have revealed that C2 binds to the N-terminal ubiquitin domain of the tobacco 40S ribosomal protein RPS27A. The C2–RPS27A connection impedes the breakdown of JAZ1, a negative regulator of JA signaling, thus hindering JA signaling and improving the performance of whitefly vectors.111 Manipulation of the JA signaling pathway by viruses may affect the attractiveness of the plants. For example, squash plants infected by cucumber mosaic virus (CMV) have become more attractive to the aphid vectors Myzus persicae and Aphis gossypii.112 The 2b protein of CMV, which is linked to the heightened preference of aphid vectors, interferes with the JA signaling pathway in plants.113 The Analysis of volatiles revealed that the 2b protein causes both quantitative and qualitative modifications to the blend of volatile products emitted by plants, which can be detected by insects. By connecting directly with JAZ proteins, the viral 2b protein can stop JA-induced JAZ degradation, thereby decreasing JA signaling and making CMV-infected plants more appealing to aphids.114,115

The SA pathway is frequently affected by viral infection. In case of the CMV sever, SA biosynthesis/catabolism and signaling activated, leading to a concurrent decline in aphid performance.116 Similarly infection of tomato plants with tobacco mosaic virus leads to increased SA biosynthesis/catabolism, which in turn elevates the levels of JA and this change in JA biosynthesis/catabolism subsequently results in the enhanced growth of Spodoptera exigua caterpillars in an SA-dependent manner.117 The infection of potato virus Y (PVY) in tomato plant increased SA biosynthesis/catabolism which is associated with improved performance of an aphid vector and two nonvector insects of PVY.118 The mechanism for virus-induced SA demonstrated that βC1, a gene encoded by the cotton leaf curl Multan virus (CLCuMuV), could increase the production of SA and its signaling by targeting WRKY20, thus providing greater resistance to the aphid Myzus persicae.118 The tomato yellow leaf curl virus C4 protein has been shown to interfere with SA synthesis through interaction with calcium receptors in the chloroplast. Targeting the SKP1-CUL1-F-box (SCF) complex to destroy the JA receptor COI1, the βC1 protein expressed by the cotton leaf curl Multan betasatellite has been demonstrated to disrupts plant ubiquitination. Inoculation of TYLCV, induced rapid accumulation of SA and JA, thus enhancing tomato plant tolerance.119 It is evident that microbial pathogens target other plant hormone signaling pathways in addition to SA, JA, and ethylene to modify host immune responses. Auxins and other virulence factors are often produced by microbial infections, which disrupt plant auxin signaling.

However, investigations have revealed that the ET signaling pathway plays a vital role in viral infection. In Arabidopsis, the performance of the aphid vector M. persicae was enhanced after infected with the turnip mosaic virus. The enhanced vector performance is due to the interference of ET signaling by the nuclear inclusion a-protease (Nla-Pro), which is encoded by the virus and causes a decrease in callose deposition, thus leading to increased palatability of the aphid vector.120 The M. persicae vector prefers to settle on potato plants infected with PVY and turnip mosaic virus, which is linked to the virus-induce biosynthesis and catabolism of ET.121 Thus, by interfering with numerous components of the plant immune signaling network, such as hormone signaling transduction and transcriptional control, microbial pathogens employ a variety of tactics to evade host immune activation. It has been demonstrated that viral infection can affect plant-insect interaction through alterations in the JA, SA and ET signaling pathways (as indicated in Table 2).Table 2. Host-mediated effects of viral infection on plant interactions.

Virus	Phytohormone biosynthesis/catabolism and signaling	Viral effector	Mechanism	References	
Tomato yellow leaf curl China virus	Downregulated JA biosynthesis/catabolism and signaling	βC1	Interaction between βC1 and MYC2	106,107	
Tomato yellow leaf curl virus	Downregulated JA signaling	?	Disruption of JA downstream defences	110	
Tomato yellow leaf curl virus	Downregulated JA signaling	C2	Interaction between C2 and ubiquitin	111	
Cotton leaf curl Multan virus and tomato yellow leaf curl China virus	Downregulated JA signaling	βC1	Interaction between βC1 and WRKY20	108	
Cucumber mosaic virus	Downregulated JA signaling	2b	Interaction between 2b and JAZ	115	
Tomato spotted wilt virus	Downregulated JA signaling	NSs	Interaction between NSs and MYC2	122	
Upregulated SA biosynthesis/catabolism and signaling	?	?	123	
Upregulated SA signaling	?	?	124	
Upregulated SA biosynthesis/catabolism and signaling and downregulated JA signaling	?	?	125,126	
Potato leafroll virus	Downregulated JA biosynthesis/catabolism	P0, P1 and P7	？	127	
Tobacco mosaic virus	Upregulated SA biosynthesis/catabolism	？	？	128	
Potato virus Y	Upregulated SA biosynthesis/catabolism	?	?	129	
Upregulated ET biosynthesis/catabolism	?	?	130	
Potato leafroll virus	Downregulated JA biosynthesis/catabolism	?	?	127	
Downregulated ET biosynthesis/catabolism	P0, P1 and P7	?	

Downstream gene expression activated by NLR proteins

When a host resistance NLR protein is activated by pathogen effectors, a series of downstream gene expression events are triggered, ultimately culminating in the initiation of plant defenses reactions.129 Among numerous known R genes, only a few have been studied in terms of the downstream signaling processes that activate HR. Resistance to TYLCV is found in wild accessions but not in domesticated tomato. The ability to recognize QTLs linked to resistance traits has enabled the identification of six QTLs, designated Ty-1 to Ty-6, to date (Table 1). However, despite the presence of Ty-2-mediated resistance, TYLCV-Mld has been documented to overcome this resistance, as evidenced by reports of resistance breakdown.130 In the 1990s, a recombinant strain of TYLCV-IS76, a combination of TYLCV-IL and TYLCSV, was generated in Morocco. This recombinant strain exhibited resistance to Ty-1, and its introduction to tomato plants harboring Ty-1 resulted in the establishment of the recombinant strain and displacement of the parental viruses.131 The identification of the p50 Avr component led to the discovery that N gene-mediated resistance in TMV infection triggered a distinct signaling pathway.45 The activation of the WIPK/SIPK-mediated MAPK cascade, triggered by wound- and/or salicylic acid-induced proteins, leads to the activation of heat shock protein 90 (HSP90), which in turn transmits defenses signals to mitochondria. This ultimately results in N gene-mediated cell death.132 It was reported that the E3 ubiquitin ligase UBR7 protein interacts directly with the TMV N protein, leading to UBR7 downregulation, which in turn increases N protein expression, thereby enhancing TMV resistance. Moreover, the TMV-p50 effector (the 50 kDa helicase domain within the 126 kDa replicase) interferes with the N-UBR7 interaction, thereby relieving the negative regulation of N.133 The disease-resistance gene Sl5R–1 against TSWV was identified through quantitative trait locus (QTL) mapping. During TSWV infection, Sl5R–1 binds to the SlTGA9 transcription factor, which enhances tomato tolerance to TSWV by interacting with or positively regulating the expression of Sl5R–1.54 Moreover, the Tsw protein directly interacts with TCP21, and the NSs of the virus intensify this interaction. The downregulation of TCP21 undermines the Tsw-mediated defenses mechanism against TSWV.43 Notably, among these transcription factors, WRKYs assume a pivotal role in orchestrating the modulation of gene expression associated with defenses mechanisms in response to pathogen invasion. During cucumber mosaic virus (CMV) infection, A. thaliana protein RCY1 collaborates with the WRKY70 transcription factor to reduce viral multiplication.134

The specific partners of the R gene, which are responsible for relaying defenses responses, have been identified. HSP90, SGT1 and PP5, which are chaperones or cochaperones, are crucial for maintaining the stability of NBS-LRR proteins and preventing them from aggregating.135 SGT1 not only functions as a chaperone but also plays a role in the defenses mechanism of the N gene and Rx gene-mediated pathways in partnership with the SCF family of E3 ubiquitin ligases.136 In general, the induction of HR is characterized by the swift production of ROS and nitric oxide (NO), the activation of various proteases, lipid peroxidation of cell membranes associated with ion fluxes, and the fortification of cell walls. However, the signaling pathway linking NLR activation and the regulation of HR gene expression has not been fully elucidated.137 Research has revealed that the formation of an oligomer from the NLR complex results in the formation of a structure known as the “resistosome”, which promotes HR-mediated cell death when the pathogen Avr is detected.36 It was observed that the CC domain of ZAR1, an NLR complex that is triggered following infection with Xanthomonas campestris pv. campestris in A. thaliana, assembles into a pentameric wheel-like resistosome structure.138,139 Recent research has shown that a novel protein, known as the “sensor NLR,” is crucial for transmitting and amplifying effector recognition signals to pathways below the surface after detecting the effector. The tomato plant exhibits a complex network of helper and sensor NLRs that interact with each other and are well-categorized in the context of different pathogens. For example, RRS1/RRS4 demonstrate resistance to the Pseudomonas syringae effector AvrRps4, while RGA5/RGA4 and PigmS/PigmR confer resistance to Magnaporthe oryzae and are referred to as “paired NLRs”.140–142 During TMV infection, the N requirement gene (NRG1), another CC-NBS-LRR-encoding R gene, contributes to TMV resistance by interacting with the N gene.143 In a recent study, it was discovered that NRG1.1 acts as a nonselective cation channel and oligomerizes within the plasma membrane of A. thaliana cells. This process triggers cell death during the hypersensitive response (HR) by enhancing the influx of cytoplasmic calcium ions.144

In addition to HR, another form of resistance known as extreme resistance (ER) has been observed in PVX infection. This form of resistance prevents viral replication without causing necrotic cell death.64 Efforts were undertaken to discover the downstream signaling pathway of Rx-1. Research has demonstrated that Ran GTPase-activating protein 2 (Ran-GAP2) plays a key role in relocating Rx-1 CNL from the cytoplasm to the nucleus when it detects Avr from PVX.69 Additionally, researchers have discovered a new type of transcription factor, NbGLK1, in N. benthamiana. In the presence of the CP106 virus, this factor binds to the GLK binding site, leading to the recruitment of the nucleus-localized Rx-1, which subsequently initiates the transcription of genes associated with the endoplasmic reticulum.145 Recent research has revealed that Rx-1 prevents the buildup of the PVX-CP protein by suppressing the translation of the CP106AVR transcript. The movement of Rx-1 between the nucleus and cytoplasm, in conjunction with the level of CP protein, determines whether the plant will respond to PVX through HR or ER.146 The N gene of N. benthamiana, a TIR-NBS-LRR, can induce translational arrest of the PVX transcript in N. benthamiana through a distinct mechanism from the Rx-1-mediated pathway, specifically via Argonaute-mediated RNA interference (RNAi).147 Despite significant progress in understanding how tomato NLR resistance genes recognize viral Avr factors and regulate downstream genes, it is important to recognize that the downstream responses to each NLR-Avr interaction are unique. Therefore, future research should focus on elucidating the molecular pathways that govern the R gene-mediated response to specific viral effectors.

Avr overcoming NLR defenses

Tomato resistance to Tobamoviruses is primarily dependent on the presence of R genes, including, Tm-1, Tm-2, and their allelic variant Tm-22. However, as viruses undergo continuous evolution and mutation, they can overcome the defenses mechanisms of tomatoes, leading to an imbalance between the R resistance gene and the Avr gene. This dynamic interaction between the plant and the virus has been extensively studied.148 The TYLCV-encoded C4 protein engages in an interaction with the tomato NLR protein Ty-1, resulting in the suppression of Ty-1-mediated antiviral defenses. This interaction facilitates the replication and dissemination of the virus within tomato plants. The discovery of the underlying molecular mechanism that govern the interplay between TYLCV and Ty-1 within tomato plants offer valuable insights into the molecular process.149 In recent years, a novel rapidly spreading RNA virus designated ToBRFV, has emerged, posing a significant threat to global tomato production and causing substantial losses within the Solanaceae family.5,150 ToBRFV belongs to the Tobamovirus genus and is closely related to TMV and ToMV. It has been demonstrated that the ToBRFV MP fails to trigger a reaction mediated by Tm-22 and that it weakens the transport capacity of ToBRFV.151 Moreover, the replacement of MP sequence of ToMV with that of ToBRFV results in the generation of a recombinant virus that can overcome Tm-22 resistance.152 Further, the research involved the use of chimeric viruses of TMV and ToBRFV, which were subjected to functional loss and gain assays. The researcher found that viruses containing ToBRFV MP could infect Tm-2-resistant plants, demonstrating that ToBRFV MP is a determinant of pathogenicity in ToBRFV-infected tomato plants harboring the Tm-22 gene. Furthermore, they successfully characterized a distinct region within the ToBRFV MP that interferes with the central domain (amino acids 60–186) of the Tm-22 resistance gene. By introducing point mutations at positions 60–186 in Tm-22, the identified six critical amino acid residues, namely, H67, N125, K129, A134, I147, and I168, were found to be indispensable for the virus to overcome the resistance mediated by Tm-22.152 These discoveries provide insight into the molecular underpinnings of Tm-22-conferred resistance and offer valuable insight into the interplay between ToBRFV and the Tm-22 resistance gene.

Exploiting host RNA silencing

In plants, RNA silencing functions as a fundamental defense mechanism, with small RNAs playing a direct regulatory role in target genes through RNA degradation or gene expression modulation. Dicer-like (DCL) proteins in plants aid in the conversion of double-stranded RNAs (dsRNAs) or hairpin RNAs into small RNAs. These small RNAs are then incorporated into Argonaute (AGO) proteins, leading to the formation of the RNA-induced silencing complex (RISC).The interaction of RISC with specific target genes enables the orchestration of sequence-specific silencing, thereby facilitating the fine-tuned regulation of gene expression.153 MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) represent the predominant class of endogenous small RNAs in plants and play a pivotal role in regulating gene expression during defenses responses against pathogenic invaders.154,155 In addition to antiviral mechanisms, an increasing body of research suggests that RNA interference (RNAi) also participates in plant defenses against nonviral pathogens. For instance, upon infection of cotton by the fungal pathogen V. dahliae, the expression of the small RNAs miR166 and miR159 is elicited.156 These microRNAs are transferred to the pathogen, initiating interkingdom silencing of virulence genes. Arabidopsis can also release extracellular vesicles containing small RNAs, which are subsequently transported to Botrytis cinerea and Phytophthora capsici, leading to the silencing of virulence genes in these pathogens.157,158 Nevertheless, certain microbial pathogens that have undergone adaptation, developed strategies to counteract RNA-silencing-mediated defenses mechanisms. Numerous RNA silencing suppressors have been identified in various microbial pathogens and hese suppressors interfere with distinct stages of the RNA silencing pathway. For example, P. sojae releases the RXLR effector PSR1, which hampers the generation of endogenous plant siRNAs, thereby impeding siRNA-mediated transgene silencing.26 The ToCV derived silencing suppressor p22, prevents the enzymatic cleavage of double-stranded RNA by DCL proteins. In contrast, the PVX viral protein P25 enhances the breakdown of AGO1 through the proteasomal degradation route. Furthermore, certain silencing suppressors exhibit distinct mechanisms of action. The P19 derived from TBSV, binds to small RNA duplexes, impeding the formation of RNA-induced silencing complexes. Conversely, in wounded N. benthamiana, the activation of Ca2+ channels depend on the calcium-binding calmodulin CAMTA3, thereby initiating RNA silencing and antiviral responses. Many proteins from Geminiviruses interfere with the binding of calmodulin CAMTA3 to suppress host RNA silencing mechanisms.159 Similarly, certain pathogens employ tactics to impede the transport of silencing RNAs. In Arabidopsis, the membrane-bound receptor-like kinases BARELY ANY MERISTEM 1 (BAM1 and BAM2) act redundantly to control the intercellular movement of small RNAs. However, the C4 protein derived from TYLCV seizes these two receptor-like kinases, thereby obstructing the intercellular movement of RNA silencing.68 It is noteworthy that certain pathogens do not eliminate RNA silencing; but utilize this mechanism to target host transcripts. The B. cinerea transports small RNAs into plant cells and these RNAs interact with AGO1 to suppress defenses-related genes. These studies reveal complex interactions between microbial pathogens and plants, providing important clues for a deeper understanding of the regulation of plant immune systems.

The Avr genes were initially identified in tobacco plants upon infection with TMV. Endogenous RNA interference (RNAi) generates small RNAs (sRNAs), including microRNAs (miRNAs) and small interfering RNAs (siRNAs), which range in length from 21 to 24 nucleotides. These sRNAs can suppress the expression of genes post-transcriptionally, thereby augmenting plant resistance against TMV infection.67,160 The defenses response of plants is rigorously regulated to suppress unnecessary harmful effects on plant growth and prevent autoimmunity caused by the overexpression of NB-LRR proteins in the uninfected state.161 Although the precise regulatory mechanisms remain unclear, research has indicated that miRNAs can cleave the transcripts of R genes under uninfected conditions, thereby maintaining R gene basal expression.156 In the case of the host tomato, miR482 and miR2118 exhibit specific binding affinity toward the Walker A (P-loop) motif present in the mRNA sequence of the CC-NLR protein. This binding interaction subsequently results in the degradation of CC-NLR mRNA. The transient expression of miR482 in N. benthamiana specifically targets the mRNA of disease-resistance proteins containing the CC-NLR domain. The mRNA degradation accompanied by the generation of secondary siRNAs, rely on the activity of RNA-dependent RNA polymerase 6 (RdRp6).162 In infected plants, the silencing cascade mediated by miR482 is repressed, resulting in enhanced expression of miR482 or secondary siRNAs that specifically target the mRNA sequence. This, in turn, leads to the prompt upregulation of NLR proteins.163 It is therefore hypothesized that plant viruses employ RNA silencing suppressors (VSRs) to reduce miRNA- and siRNA-mediated inhibition of R genes and induce downstream HR.164 The previous study revealed the crucial involvement of DCL2 as the primary dicer endonuclease in tomato defenses against TMV and PVX. Their findings demonstrated that the synthesis of miR6026 necessitates the presence of the SlDCL2 protein. Furthermore, miRNA6026 can specifically target and degrade the SlDCL2 mRNA, thereby initiating the generation of novel siRNAs and activating the production of secondary siRNAs. This cascade establishes a feedback regulatory system. Notably, a reduction in miR6026 levels results in an increase in SlDCL2 expression, thereby enhancing plant resistance to viral infections.164,165 A study was conducted to investigate the noncoding intergenic region (IR) of TYLCV and its impact on tomato plants. The findings revealed that TYLCV infection induces bidirectional transcription within the IR, leading to the manifestation of aberrant phenotypes in plants. Through sequencing, it was discovered that the IR region produces a substantial quantity of siRNAs that specifically target a long non-coding RNA gene known as SlLNR1 in susceptible tomato varieties. Consequently, SlLNR1 is degraded, resulting in deformities and reduced resistance against TYLCV.166 Furthermore, the overexpression of SlLNR1 has been shown to enhance plant resistance against TYLCV. Recent investigations have revealed that Sw-5a can recognize the AC4 protein derived from tomato leaf curl New Delhi virus (ToLCNDV), subsequently initiates an HR in tomato plants. The miR159-Myb33 regulates the expression of Sw-5a and improves resistance against virus in tomato.66 In addition to the antiviral regulatory mechanisms governed by miRNAs and siRNAs, the regulation of R gene expression and the interaction of the transcription factor WRKY with the promoter regions of NLR genes contribute to the modulation of NLR-associated signaling defenses systems.167 Avr genes are considered promising tools for developing virus-resistant crops. The introduction of Avr genes into crop plants enables the conferral of resistance against a broad spectrum of plant viruses, including those that present economic challenges and are difficult to control using alternative approaches.

Conclusion and future perspectives

Viral effector mutations can alter effector structures, hinder the recognition of the R resistance genes in tomato plants, and restrict the transfer and design of new specific effective NLRs. The stacking of immune receptor genes is a strategy for preventing microbial evasion of host immunity that has gained widespread recognition.167 For instance, the introduction of five NLRs into bread wheat can confer robust and comprehensive resistance against highly virulent and invasive isolates of Puccinia graminis f. sp. tritici. In field trials, the P. graminis isolates were found to be unable to escape recognition by all five resistance genes, thus providing a promising outlook for durable resistance. Furthermore, durable disease resistance can be achieved by inactivating susceptible S genes (sensor NLRs). A typical case of the MILDEW RESISTANCE LOCUS O (MLO) gene homologous to S gene, whose inactivation in wheat enhances tolerance against powdery mildew.168 Combining the stacking of R genes with the inactivation of S genes could be a novel approach to enhancing resistance in tomato breeding. Nevertheless, a counterargument to the utilization of stacking methods is that such an approach imposes substantial selection pressure on microbial pathogens, which may expedite the evolution of super pathogens and contribute to the emergence of uncontrollable disease outbreaks.

An additional strategy to augment the immune response involves the utilization of engineered sensor NLRs (such as Rx and SW5b) and expanding their recognition specificity through stepwise artificial evolution. This approach effectively broadens the range of resistance against various viral isolates. Similarly, structure-guided editing of the rice immune sensor Pikp enhanced its ability to recognize previously unidentified AVR-Pik variants. The successful interference with microbial effector activity has been achieved through the engineering of host targets. The implementation of “bait” engineering, which entails the design of the recognition specificity of plant NLRs, holds great promise as an effective approach to combat viruses. During the infection of A. thaliana by Pseudomonas syringae, the cysteine protease AvrPphB triggers the activation of the immune sensor RPS5 through the cleavage of PBS1. By modifying the cleavage site of PBS1 targeted by AvrPphB, RPS5 can be activated by alternative pathogen proteases, consequently enhancing RPS5-mediated resistance against other pathogens. Similarly, resistance genes were engineered to expand the recognition specificity and enhance resistance against viral isolates. An alternative illustration is the artificial modification of the promoter region of the Tsw gene, which has been found to enhance resistance against TSWV in an SGT1 (suppressor of G2 allele of Skp1)-dependent manner.169 Moreover, RNA interference (RNAi) is an important antiviral mechanism, and the redesigning of RNAi pathway can increase tomato plant tolerance. The silencing of the key gene SlAGO1 within the tomato RNAi pathway has been demonstrated to reduce resistance to the TYLCV virus.170 Similarly, the silencing of the key genes SlDCL2/4 has been shown to disrupt the TYLCV resistance markers Ty-1/Ty-3, and silencing of the viral proteins V1 and C1 has been observed to enhance plant tolerance.165 Despite the identification of numerous effector targets, only a limited number of core targets play a role in the immune recognition of Avr proteins. In the future, a comprehensive exploration of plant immune receptors and core signaling pathways can be accomplished through the utilization of high-throughput techniques, such as pan-genomics and whole-genome analysis. Such approaches have the potential to unveil a distinct gene set that can in turn enhance plant immunity against pathogens that are rapidly evolving.

However, the effects of global climate change and human-driven breeding preferences have severely compromised the resistance mechanisms of tomato plants. The recently reported ToBRFV has led to a sharp decline in the expression of host R resistance genes. Consequently, there is an urgent need to explore and screen for new sources of resistance materials to cope with ToBRFV and potential future outbreaks of plant pathogens. Utilizing known R genes to intervene in resistance will help elucidate complex resistance mechanisms and provide theoretical support for related breeding efforts. For viruses similar to ToBRFV, which cause widespread outbreaks and lack resistant varieties, the following approaches can be considered: (1) cross-protection control through screening for mild virus strains; (2) exploring antiviral resources in wild tomato germplasms; (3) selecting resistant new germplasms through population mutagenesis; and (4) precise breeding using genetic engineering techniques to provide rapid and effective solutions. These strategies will contribute to effectively addressing such viral threats in the short term.

Acknowledgments

These images were created from the website https://app.biorender.com/. We thank Professor Wen Xu, Jianmin Yan of the College of Agriculture, Guizhou University, for providing technical support throughout this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

W. J. and T. P. conceived the contents of the manuscript. W. J. wrote the manuscript. T.M revised the manuscript. L. YZ., C. X and L. Y. finalized the writing and revision of the manuscript. All the authors have read and approved the final version of the manuscript.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
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