IFITM3 Deficiency Drives SARS-CoV-2 Adaptation While Preserving Variant-Specific Traits

Here we investigated whether interferon-induced transmembrane protein 3 (IFITM3), a key antiviral protein deficient in certain human populations, affects interspecies adaptation of SARS-CoV-2. We found that SARS-CoV-2 Beta and Omicron variants passaged through IFITM3-deficient versus wild type mice exhibit enhanced replication and pathogenesis in this new host species. Enhancements were associated with amino acid substitutions in the viral genome, suggesting that IFITM3 limits accumulation of adaptive mutations. Mouse-adapted viruses enabled comparative studies of variants in mice. Beta caused lung dysfunction and altered cilia-associated gene programs, consistent with broad viral antigen distribution in the lungs. Omicron, which shows low pathogenicity and upper respiratory tract preference in humans, replicated to high nasal titers while exhibiting limited lung spread and reduced inflammatory responses compared to Beta. Our findings demonstrate that IFITM3 deficiency accelerates SARS-CoV-2 adaptation while preserving pre-existing variant-specific properties, highlighting that host adaptation enhances viral fitness without necessarily overriding intrinsic viral characteristics.