
==== Front
bioRxiv
BIORXIV
bioRxiv
Cold Spring Harbor Laboratory

10.1101/2024.05.23.595578
preprint
1
Article
Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread
Pahmeier Felix http://orcid.org/0000-0002-7445-2259

Monticelli Stephanie R. http://orcid.org/0000-0002-5031-2534

Feng Xinyi
Hjorth Christy K. http://orcid.org/0000-0003-2324-8984

Wang Albert
Kuehne Ana I.
Bakken Russell R.
Batchelor Thomas G.
Lee Saeyoung E.
Middlecamp Marissa
Stuart Lauren
Abelson Dafna M.
McLellan Jason S.
Biering Scott B. http://orcid.org/0000-0003-1991-629X

Herbert Andrew S.
Chandran Kartik http://orcid.org/0000-0003-0232-7077

Harris Eva http://orcid.org/0000-0002-7238-4037

23 5 2024
2024.05.23.595578http://biorxiv.org/lookup/doi/10.1101/2024.05.23.595578
nihpp-2024.05.23.595578.pdf
Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells secrete the viral glycoprotein GP38, whose extracellular function is presently unknown. GP38 is considered an important target for vaccine and therapeutic design as GP38-specific antibodies can protect against severe disease in animal models, albeit through a currently unknown mechanism of action. Here, we show that GP38 induces endothelial barrier dysfunction in vitro , and that CCHFV infection, and GP38 alone, can trigger vascular leak in a mouse model. Protective antibodies that recognize specific antigenic sites on GP38, but not a protective neutralizing antibody binding the structural protein Gc, potently inhibit endothelial hyperpermeability in vitro and vascular leak in vivo during CCHFV infection. This work uncovers a function of the secreted viral protein GP38 as a viral toxin in CCHFV pathogenesis and elucidates the mode of action of non-neutralizing GP38-specific antibodies.
==== Body
pmc
