Antibodies targeting the Crimean-Congo Hemorrhagic Fever Virus nucleoprotein protect via TRIM21

Shanna S. Leventhal, Thomas Bisom, Dean Clift, Deepashri Rao, Kimberly Meade-White, Carl Shaia, Justin Murray, Evan A. Mihalakakos, Troy Hinkley, Steven J. Reynolds, Sonja M. Best, Jesse H. Erasmus, Leo C. James, Heinz Feldmann () and David W. Hawman ()
Additional contact information
Shanna S. Leventhal: Rocky Mountain Laboratories
Thomas Bisom: Rocky Mountain Laboratories
Dean Clift: Medical Research Council Laboratory of Molecular Biology
Deepashri Rao: Rocky Mountain Laboratories
Kimberly Meade-White: Rocky Mountain Laboratories
Carl Shaia: Rocky Mountain Laboratories
Justin Murray: Rocky Mountain Laboratories
Evan A. Mihalakakos: Rocky Mountain Laboratories
Troy Hinkley: HDT Bio
Steven J. Reynolds: USA; Johns Hopkins School of Medicine
Sonja M. Best: Rocky Mountain Laboratories
Jesse H. Erasmus: HDT Bio
Leo C. James: Medical Research Council Laboratory of Molecular Biology
Heinz Feldmann: Rocky Mountain Laboratories
David W. Hawman: Rocky Mountain Laboratories

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a negative-sense RNA virus spread by Hyalomma genus ticks across Europe, Asia, and Africa. CCHF disease begins as a non-specific febrile illness which may progress into a severe hemorrhagic disease with no widely approved or highly efficacious interventions currently available. Recently, we reported a self-replicating, alphavirus-based RNA vaccine that expresses the CCHFV nucleoprotein and is protective against lethal CCHFV disease in mice. This vaccine induces high titers of non-neutralizing anti-NP antibodies and we show here that protection does not require Fc-gamma receptors or complement. Instead, vaccinated mice deficient in the intracellular Fc-receptor TRIM21 were unable to control the infection despite mounting robust CCHFV-specific immunity. We also show that passive transfer of NP-immune sera confers significant TRIM21-dependent protection against lethal CCHFV challenge. Together our data identifies TRIM21-mediated mechanisms as the Fc effector function of protective antibodies against the CCHFV NP and provides mechanistic insight into how vaccines against the CCHFV NP confer protection.

Date: 2024
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DOI: 10.1038/s41467-024-53362-7

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