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Principal Investigator: Kartik Chandran
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $558,501
Funding agency: National Institute of Allergy and Infectious Diseases
The nairovirus Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe, lethal hemorrhagic disease.
CCHFV is the most prevalent tickborne virus that causes human disease and is endemic in countries across
Europe, Asia, and Africa. No FDA-approved countermeasures are currently available for this NIAID priority
pathogen. As in other bunyaviruses, the viral M segment of CCHFV encodes the glycoprotein precursor, GPC,
which undergoes an especially complicated series of co- and post-translational proteolytic processing steps to
generate multiple membrane-anchored, membrane-associated, and secreted glycoproteins. The overarching
goal of this highly interwoven collaborative project is to address the critical gaps in our understanding of the
architecture and assembly of the membrane-bound, virion-incorporated, and secreted glycoprotein
components and complexes, and their functions in virion assembly, entry, host cell subversion, and disease.
The collaborative team is anchored by K. Chandran (Einstein; BSL-2 virus models, genetic approaches,
mechanistic virology, antibody discovery), J. McLellan (UT-Austin; structural virology, protein engineering), E.
Harris (UC-Berkeley; virus-host interactions underlying pathogenesis, viral toxins), and A. Herbert and S.
Monticelli (USAMRIID/The Geneva Foundation; mechanisms of infection and pathogenesis by authentic viruses
at BSL-4). We also leverage the unique expertise of S. Sidoli (Einstein; mass spectrometry). Rigorous
preliminary research by our interdisciplinary team has uncovered evidence that GP38 is both an integral
component of the CCHFV entry glycoprotein complex and a secreted `toxin' that can subvert host
endothelial barriers to cause vascular leak and/or facilitate viral dissemination. Building on these and other
findings, we will determine high-resolution structures of CCHFV glycoprotein complexes and discover novel
human monoclonal antibodies (Aim 1); elucidate mechanisms of CCHFV assembly, entry, and antibody action
(Aim 2); and uncover entry-independent mechanisms of viral pathogenesis mediated by CCHFV GP38 and
investigate the mechanisms by which anti-GP38 antibodies protect against CCHV infection and disease (Aim 3).
We expect to deliver analyses of the structure, assembly, and functions of the `Swiss army knife' that is the
CCHFV glycoprotein complex at an unprecedented level of molecular detail and identify viral Achilles' heels for
the development of urgently needed CCHFV medical countermeasures.
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