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

Area of Science:

• Virology
• Immunology
• Pathology

Background:

• Sex-based disparities in COVID-19 outcomes are evident but poorly understood concerning specific SARS-CoV-2 variants.
• Individual variants like Omicron and Delta elicit distinct pathological responses.

Purpose of the Study:

• To investigate sex-specific differences in host responses and pathology following infection with SARS-CoV-2 variants (614G, Delta, Omicron).
• To elucidate variant-specific immune cell infiltration and cytokine profiles in a sex-stratified manner.

Main Methods:

• Utilized K18-hACE2 transgenic mice (female and male) infected with SARS-CoV-2 614G, Delta, or Omicron variants.
• Analyzed lung and nasal cavity tissues for pathological changes, immune cell infiltration (macrophages, neutrophils, NK cells, T cells), and cytokine expression.
• Employed lung spatial transcriptomics to identify sex-specific gene pathway enrichment.

Main Results:

• Delta variant induced the most severe nasal and lung pathology, followed by 614G, then Omicron.
• Delta-infected males showed increased M2 macrophages, neutrophils, NK cells, and inflammatory cytokines (IL-10, IL-6, IP-10) compared to females.
• Omicron-infected females had increased CD4+ T cell recruitment, while Delta-infected females showed elevated MCP-1 compared to males.
• Spatial transcriptomics revealed variant-specific, sex-biased gene pathway enrichment related to immune response, inflammation, and extracellular matrix production.

Conclusions:

• Host responses to SARS-CoV-2 infection are significantly influenced by both the specific viral variant and the host's sex.
• Sex is a critical factor modulating COVID-19 pathology and immune dynamics, necessitating sex-stratified research and clinical considerations.