Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread

Area of Science:

• Virology
• Immunology
• Pathogenesis

Background:

• Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen causing severe disease with no approved vaccines or therapeutics.
• Endothelial dysfunction, hemorrhage, and multiorgan failure are hallmarks of severe CCHFV.
• The extracellular function of the secreted viral glycoprotein GP38 is unknown, despite its importance as a vaccine and therapeutic target.

Purpose of the Study:

• To investigate the extracellular function of CCHFV glycoprotein GP38.
• To determine GP38's role in CCHFV-induced vascular leak.
• To elucidate the mechanism of action for protective GP38-specific antibodies.

Main Methods:

• In vitro assays to assess GP38's effect on endothelial barrier function.
• In vivo mouse models of CCHFV infection to evaluate vascular leak.
• Analysis of antibody efficacy against GP38 and the Gc protein in inhibiting vascular leak.

Main Results:

• GP38 was shown to induce endothelial barrier dysfunction in vitro.
• Both CCHFV infection and GP38 alone triggered vascular leak in a mouse model.
• Non-neutralizing antibodies targeting specific GP38 epitopes potently inhibited endothelial hyperpermeability and vascular leak, while a neutralizing antibody against Gc did not.

Conclusions:

• The secreted viral protein GP38 functions as a viral toxin contributing to CCHFV pathogenesis.
• GP38 induces vascular leak by disrupting the endothelial barrier.
• Non-neutralizing antibodies targeting GP38 offer protection by inhibiting this toxic function, revealing a novel therapeutic strategy.