Male and female mice achieve equivalent protection against heterologous SARS-CoV-2 infection through divergent immune mechanisms.

UNLABELLED: 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 IFNγ-associated myeloid inflammation upon secondary Delta infection. Using lymphoid-deficient mice that display female-biased resistance to Delta infection, IFNγ treatment provides partial protection to naïve 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.

ONE-SENTENCE SUMMARY: Male and female mice show equivalent protection against secondary heterologous SARS-CoV-2 infection; however, females rely on controlled, rapid myeloid-associated inflammatory responses, while males rely on conventional B- and T-cell-mediated responses.