The Intestinal Microbiome Differentially Modulates SARS-CoV-2-Induced Pathology and Host Immune Response in Male and Female Mice 2261020

Abstract Introduction Several reports have shown disparity in male and female responses to SARS-CoV-2 infection. Males often develop move severe acute infection, while the incidence of females developing long-COVID out-numbers males. Commensal microbes play a vital role in shaping both the mucosal and systemic immune response to pathogens. Using germ-free mice, we investigated whether commensal microbes play a role in male and female host susceptibility to SARS-Cov-2 infection. Methods Age-matched male and female germ-free (GF) and control specific pathogen free (SPF) C57BL/6 mice were intranasally infected with the mouse-adapted SARS-CoV-2 MA10. Body weight, temperature, and behavior scores were monitored to assess the severity of disease. Innate responses in the lungs and peripheral blood were determined by flow cytometry analysis of innate subsets, viral load in lung tissues, and the profile of host mRNA responses. Results Male and female GF mice differentially responded to SARS-CoV-2 infection. Thus, female GF mice also showed no change in body temperature, while the infected male GF mice displayed the characteristic drop in body temperature seen in SPF C57BL/6 mice. However, neither male nor female GF mice lost weight after infection. Blood collected three days post infection, showed higher numbers of CD11b+CD11c+ and CD11b+Ly6G+ cells in male GF compared to female GF mice. Further, the lungs of male GF mice contained higher titers of live SARS-CoV-2 MA10 virus than female GF mice four days post infection. Ongoing scRNAseq analysis of male and female GF mice lungs are expected to identify mechanisms underlying these differences. Conclusion Our results suggest that commensal microbes-dependent and -independent mechanisms contribute to the difference of outcome after SARS-CoV-2 infection of males and females. Cellular and molecular mechanisms underlying these differences are being investigated. Funding Source NIH P01AI175399 Topic Categories Mucosal and Regional Immunology (MUC)