Dissecting Sex-Specific Pathology in K18-hACE2 Transgenic Mice Infected With Different SARS-CoV-2 Variants

Sex-biased differences in COVID-19 outcomes in relation to individual SARS-CoV-2 variants are not well understood. In this study, lungs and nasal cavities of age-matched female and male K18-hACE2 transgenic mice were collected for dissecting sex-specific differences in pathology after infection of SARS-CoV-2 614 G, Delta, or Omicron variant. Overall, Delta infection induced the most severe inflammation and pathology in nasal cavity and lung followed by the 614 G, then Omicron variant. Sex differences in host responses to SARS-CoV-2 infection were variant-specific. Delta-infected males showed increased pulmonary infiltration of CD163+ "M2" macrophages, Ly6G+ neutrophils, and NKR-P1C + NK cells during early onset of infection, and elevated lung inflammatory cytokines such as IL-10, IL-6, and IP-10 than Delta-infected females. Conversely, females had increased lung CD4 + T cell recruitment after Omicron infection and significantly elevated lung MCP-1 secretion after Delta infection than males. Lung spatial transcriptomics data revealed that Delta-infected females had enriched gene pathways related to humoral immune response and interferon signaling, while males had enriched pathways associated with extracellular matrix production, chemokine signaling, and cell chemotaxis. Taken together, this study highlights the complex infection dynamics with respect to individual SARS-CoV-2 variants and underscores the importance of sex as a confounding factor for COVID-19 pathology.