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

• Published in: Nature communications Vol. 15; no. 1; pp. 9236 - 14
• Main Authors: Leventhal, Shanna S., Bisom, Thomas, Clift, Dean, Rao, Deepashri, Meade-White, Kimberly, Shaia, Carl, Murray, Justin, Mihalakakos, Evan A., Hinkley, Troy, Reynolds, Steven J., Best, Sonja M., Erasmus, Jesse H., James, Leo C., Feldmann, Heinz, Hawman, David W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/2152/2153/1291; 631/326/590/2293; 631/326/596; 64; 64/110; Animals; Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antisera; Crimean hemorrhagic fever; Fc receptors; Female; Fever; Hemorrhagic disease; Hemorrhagic Fever Virus, Crimean-Congo - immunology; Hemorrhagic Fever, Crimean - immunology; Hemorrhagic Fever, Crimean - prevention & control; Humanities and Social Sciences; Humans; Immune system; Immunization, Passive; Infectious diseases; Intracellular; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neutralizing; Nucleoproteins - immunology; Nucleoproteins - metabolism; Receptor mechanisms; Receptors; Ribonucleoproteins - immunology; Ribonucleoproteins - metabolism; RNA viruses; Robust control; Science; Science (multidisciplinary); Ticks; Vaccines; Viral Vaccines - immunology; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53362-7

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. Non-neutralizing antibodies against the nucleoprotein (NP) of Crimean-Congo hemorrhagic fever virus are protective against lethal challenge in mice. Here, the authors show that these anti-NP antibodies protect through the intracellular antibody receptor TRIM21 and that protection is independent of T cells.