Phosphatidylserine receptors are critical for lethal infection by Crimean-Congo hemorrhagic fever virus
- 1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Montefiore-Einstein Comprehensive Cancer Center, Albert Ei
Abstract
The tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe and often fatal hemorrhagic disease for which no approved countermeasures are available. Herein, we identify the phosphatidylserine receptors (PSRs) AXL, TIM-1, and TIM-4 as critical entry host factors for CCHFV in cell lines and liver-derived primary cell cultures. Small-molecule and antibody-based PSR inhibitors greatly reduced viral infection in cell culture. Germline knockout of individual PSR genes afforded partial protection against CCHFV infection, disease, and death in a murine model of lethal viral challenge. Mice engineered to lack two PSRs were completely protected from challenge, with viremia and viral replication, pathology, and inflammation in the liver and spleen reduced to baseline. Therefore, PSRs are collectively indispensable for CCHFV infection and pathogenesis. We conclude that PSRs are not just cell entry factors but bona fide determinants of infection, dissemination, and disease by CCHFV and legitimate targets for the development of new antiviral countermeasures.
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BibTeX
@misc{berrigan2026phosphatidylserine,
title = {{Phosphatidylserine receptors are critical for lethal infection by Crimean-Congo hemorrhagic fever virus}},
author = {J. Berrigan and S. R. Monticelli and M. D. Ramirez and P. T. Donovan and T. S. Powell and A. I. Kuehne and R. R. Bakken and S. B. Sulkosky and S. R. Coyne and X. Zeng and C. P. Stefan and A. S. Herbert and W. J. Maury and K. Chandran and E. Kasikci},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.29.762781},
url = {https://www.biorxiv.org/content/10.64898/2026.10.29.762781v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Phosphatidylserine receptors are critical for lethal infection by Crimean-Congo hemorrhagic fever virus
AU - J. Berrigan
AU - S. R. Monticelli
AU - M. D. Ramirez
AU - P. T. Donovan
AU - T. S. Powell
AU - A. I. Kuehne
AU - R. R. Bakken
AU - S. B. Sulkosky
AU - S. R. Coyne
AU - X. Zeng
AU - C. P. Stefan
AU - A. S. Herbert
AU - W. J. Maury
AU - K. Chandran
AU - E. Kasikci
PY - 2026
DA - 2026/10/29
PB - bioRxiv
DO - 10.64898/2026.10.29.762781
UR - https://www.biorxiv.org/content/10.64898/2026.10.29.762781v1
AB - The tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe and often fatal hemorrhagic disease for which no approved countermeasures are available. Herein, we identify the phosphatidylserine receptors (PSRs) AXL, TIM-1, and TIM-4 as critical entry host factors for CCHFV in cell lines and liver-derived primary cell cultures. Small-molecule and antibody-based PSR inhibitors greatly reduced viral infection in cell culture. Germline knockout of individual PSR genes afforded partial protection against CCHFV infection, disease, and death in a murine model of lethal viral challenge. Mice engineered to lack two PSRs were completely protected from challenge, with viremia and viral replication, pathology, and inflammation in the liver and spleen reduced to baseline. Therefore, PSRs are collectively indispensable for CCHFV infection and pathogenesis. We conclude that PSRs are not just cell entry factors but bona fide determinants of infection, dissemination, and disease by CCHFV and legitimate targets for the development of new antiviral countermeasures.
ER -