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Publication Abstract from PubMed

Crimean-Congo hemorrhagic fever virus (CCHFV) is the causative agent of the most widespread tick-borne viral infection in humans. CCHFV encodes a secreted glycoprotein (GP38) of unknown function that is the target of a protective antibody. Here we present the crystal structure of GP38 at a resolution of 2.5 A, which revealed a novel fold primarily consisting of a 3-helix bundle and a beta-sandwich. Sequence alignment and homology modeling showed distant homology between GP38 and the ectodomain of Gn (a structural glycoprotein in CCHFV), suggestive of a gene duplication event. Analysis of convalescent sera showed high titers of GP38 antibodies indicating immunogenicity in humans during natural CCHFV infection. The only protective antibody for CCHFV in an adult mouse model reported to date, 13G8, bound GP38 with sub-nanomolar affinity and protected against heterologous CCHFV challenge in a STAT1-knockout mouse model. Our data strongly suggests that GP38 should be evaluated as a vaccine antigen and its structure provides a foundation to investigate functions of this protein in the viral life cycle.IMPORTANCECrimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen that poses a high risk to public health. Due to the high morbidity and mortality rates associated with CCHFV infection, there is an urgent need for developing medical countermeasures for disease prevention and treatment. CCHFV GP38, a secreted glycoprotein of unknown function unique to the Nairoviridae family, was recently shown to be the target of a protective antibody against CCHFV. Here we present the crystal structure of GP38, which revealed a novel fold with distant homology to another CCHFV glycoprotein that is suggestive of a gene duplication event. We also demonstrate that antibody 13G8 protects STAT1-knockout mice against heterologous CCHFV challenge using a clinical isolate from a CCHFV endemic region. Collectively, these data advance our understanding of GP38 structure and antigenicity and should facilitate future studies investigating its function.

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38.,Mishra AK, Moyer CL, Abelson DM, Deer DJ, El Omari K, Duman R, Lobel L, Lutwama JJ, Dye JM, Wagner A, Chandran K, Cross RW, Geisbert TW, Zeitlin L, Bornholdt ZA, McLellan JS J Virol. 2020 Jan 29. pii: JVI.02005-19. doi: 10.1128/JVI.02005-19. PMID:31996434^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.