IFITM3 deficiency drives SARS-CoV-2 adaptation while preserving variant-specific traits.

SARS-CoV-2 can infect and adapt to multiple animal species, yet the host determinants that control interspecies viral adaptation remain poorly defined. Here we investigate whether interferon-induced transmembrane protein 3 (IFITM3), a key antiviral protein deficient in certain human populations, affects interspecies adaptation of SARS-CoV-2. We find that SARS-CoV-2 Beta and Omicron BA.4 variants passaged through IFITM3-deficient versus wild type mice exhibit enhanced replication and pathogenesis in this new host species. These enhancements are associated with amino acid substitutions in the viral genome, suggesting that IFITM3 limits accumulation of adaptive mutations. Mouse-adapted viruses enable comparative studies of variants in mice. Beta causes lung dysfunction and alters cilia-associated gene programs, consistent with broad viral antigen distribution in the lungs. Omicron, which shows mild pathogenicity and upper respiratory tract preference in humans, replicates 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.