Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread
Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread
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.
Batchelor Thomas G.、Herbert Andrew S.、Chandran Kartik、Abelson Dafna M.、Bakken Russell R.、Lee Saeyoung E.、Stuart Lauren、McLellan Jason S.、Feng Xinyi、Hjorth Christy K.、Pahmeier Felix、Middlecamp Marissa、Monticelli Stephanie R.、Wang Albert、Biering Scott B.、Kuehne Ana I.、Harris Eva
Viral Immunology Branch, U.S. Army Medical Research Institute of Infectious Diseases||Oak Ridge Institute of Science EducationViral Immunology Branch, U.S. Army Medical Research Institute of Infectious DiseasesDepartment of Microbiology and Immunology, Albert Einstein College of MedicineMapp Biopharmaceutical, Inc.Viral Immunology Branch, U.S. Army Medical Research Institute of Infectious DiseasesDivision of Infectious Diseases and Vaccinology, School of Public Health, University of CaliforniaMapp Biopharmaceutical, Inc.Department of Molecular Biosciences, The University of Texas at AustinDivision of Infectious Diseases and Vaccinology, School of Public Health, University of CaliforniaDepartment of Molecular Biosciences, The University of Texas at AustinDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California||Infectious Diseases and Immunity Graduate Group, School of Public Health, University of CaliforniaMapp Biopharmaceutical, Inc.Viral Immunology Branch, U.S. Army Medical Research Institute of Infectious Diseases||The Geneva FoundationDepartment of Microbiology and Immunology, Albert Einstein College of MedicineDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California||Department of Molecular Biology, School of Biological Sciences, University of CaliforniaViral Immunology Branch, U.S. Army Medical Research Institute of Infectious DiseasesDivision of Infectious Diseases and Vaccinology, School of Public Health, University of California
基础医学微生物学生物科学研究方法、生物科学研究技术
Batchelor Thomas G.,Herbert Andrew S.,Chandran Kartik,Abelson Dafna M.,Bakken Russell R.,Lee Saeyoung E.,Stuart Lauren,McLellan Jason S.,Feng Xinyi,Hjorth Christy K.,Pahmeier Felix,Middlecamp Marissa,Monticelli Stephanie R.,Wang Albert,Biering Scott B.,Kuehne Ana I.,Harris Eva.Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2024.05.23.595578.点此复制
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