Severe disease following infection with SARS-CoV or SARS-CoV-2 is driven in part by genetically regulated immune responses that promote lung injury. To study genetic mechanisms of immune-mediated coronavirus pathogenesis, we screened the Collaborative Cross (CC) panel for Mus musculus strains that are phenotypically divergent with respect to coronavirus susceptibility. We identified CC006/TauUnc and CC044/UncJ as susceptible and resistant, respectively, and crossed them in an intercross to produce a genetic mapping population. Previously, we mapped genetic loci associated with disease severity, including HrS43, which is both conserved across viruses and between mouse and human. Here, we incorporate immune cell data from flow cytometry and perform a systems genetics analysis to resolve immune pathways linking host genetic loci to disease outcomes. We identify: (1) immune predictors of disease severity, as revealed by Bayesian variable selection; (2) extensive genetic regulation of the immune system at homeostasis and in response to infection, as revealed by infection-stratified and combined genotype-by-treatment (GxT) QTL mapping; and (3) candidate causal pathways linking genetic loci, immune responses, and disease severity, as revealed by context-dependent Bayesian mediation analysis. Our analysis reveals distinct patterns of virus specificity across biological layers: immune effects on disease severity appear largely consistent across viruses; genetic architecture is both shared and virus-specific; and mediating immune traits are in most cases virus-dependent. Notably, HrS43 appears to influence disease severity through distinct immune mediators in SARS-CoV versus SARS-CoV-2, demonstrating that conserved genetic susceptibility can drive virus-specific immunopathology with translational relevance across species.
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