Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms
- 1Boston University
Abstract
Biological sex is a major determinant of antiviral immunity, yet how it shapes lung-resident antiviral immunity remains poorly understood. We report that prior mild SARS-CoV-2 BA.1 infection protects mice from lethal heterologous Delta challenge through distinct sex-biased immune mechanisms. Although heterologous protection is clinically equivalent between sexes, T- and B-cell depletions before BA.1 exposure abrogate protection only in males. Depletion with anti-CD4, but not anti-CD8, abolishes protection in both sexes, but co-depletion with anti-CD4/anti-CD8 partially restores protection in females only. Further, females exhibit enhanced IFN-gamma-associated myeloid inflammation upon secondary Delta infection. Using lymphoid-deficient mice that display female-biased resistance to Delta infection, IFN-gamma treatment provides partial protection to naive males against Delta. Female resistance is lost after previous BA.1 exposure, highlighting the importance of lymphoid-mediated inflammatory regulation. Together, equivalent antiviral protection against heterologous respiratory viral infection is governed by sexually dimorphic mechanisms, with significant implications for designing mucosal vaccines and immunotherapies.
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BibTeX
@misc{kenney2026male,
title = {{Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms}},
author = {D. Kenney and M. Matsuo and A. Pantelias and J. Leger and A. Kaplan and F. Cerbo and D.-Y. Chen and S. Adams and G. Unali and D. Wallace and M. Saeed and A. Belkina and C. Harly and F. Douam},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755090},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755090v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms
AU - D. Kenney
AU - M. Matsuo
AU - A. Pantelias
AU - J. Leger
AU - A. Kaplan
AU - F. Cerbo
AU - D.-Y. Chen
AU - S. Adams
AU - G. Unali
AU - D. Wallace
AU - M. Saeed
AU - A. Belkina
AU - C. Harly
AU - F. Douam
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755090
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755090v1
AB - Biological sex is a major determinant of antiviral immunity, yet how it shapes lung-resident antiviral immunity remains poorly understood. We report that prior mild SARS-CoV-2 BA.1 infection protects mice from lethal heterologous Delta challenge through distinct sex-biased immune mechanisms. Although heterologous protection is clinically equivalent between sexes, T- and B-cell depletions before BA.1 exposure abrogate protection only in males. Depletion with anti-CD4, but not anti-CD8, abolishes protection in both sexes, but co-depletion with anti-CD4/anti-CD8 partially restores protection in females only. Further, females exhibit enhanced IFN-gamma-associated myeloid inflammation upon secondary Delta infection. Using lymphoid-deficient mice that display female-biased resistance to Delta infection, IFN-gamma treatment provides partial protection to naive males against Delta. Female resistance is lost after previous BA.1 exposure, highlighting the importance of lymphoid-mediated inflammatory regulation. Together, equivalent antiviral protection against heterologous respiratory viral infection is governed by sexually dimorphic mechanisms, with significant implications for designing mucosal vaccines and immunotherapies.
ER -