SARS-CoV-2 XBB.1.5 infects wild-type C57BL/6 mice and induces a protective CD4

Mouse models are critical for studying SARS-CoV-2 pathogenesis and evaluating therapeutic and preventive strategies. Standard C57BL/6 mice are generally resistant to infection with the ancestral SARS-CoV-2 strain due to inefficient binding of the viral spike protein to the murine angiotensin-converting enzyme 2 (ACE2) receptor. Although human ACE2 transgenic mice can support robust pulmonary infection, these models often develop fatal encephalitis, a pathology not commonly observed in humans. We and others have previously shown that certain SARS-CoV-2 variants can infect wild-type C57BL/6 mice and cause discernible disease. However, the susceptibility of C57BL/6 mice to recently emerged Omicron subvariants, and the role of T cell-mediated immunity in controlling these infections, remain incompletely understood. Herein, we evaluated the susceptibility of wild-type C57BL/6 mice to infection with the SARS-CoV-2 Omicron subvariant XBB.1.5. We assessed viral burden, innate and adaptive immune responses, and virus-induced lung pathology. Our findings demonstrate that XBB.1.5 efficiently replicates in both the upper and lower respiratory tracts of C57BL/6 mice, inducing significant lung inflammation and pathology. Infection elicited a robust pulmonary CD4