SARS-CoV-2 spike-armed vesicular stomatitis virus recapitulates severe COVID-19 acute respiratory distress syndrome in mice.

Clinically relevant preclinical models are critical for understanding acute respiratory distress syndrome (ARDS) and developing novel therapeutics. Although SARS-CoV-2 pseudovirus-based models overcome biosafety challenges associated with live coronavirus, their ability to recapitulate key ARDS features and respond to established treatment remains unclear. We developed a vesicular stomatitis virus expressing the SARS-CoV-2 spike protein (VSV-CoV2-S) for safe use in BSL-2 facilities. We evaluated its ability to induce acute lung injury (ALI) and its responsiveness to dexamethasone. Intratracheal inoculation of K18-hACE2 transgenic mice induced severe ALI characterized by alveolar damage, pulmonary hemorrhage, vascular hyperpermeability, inflammatory cytokine production, and immune cell infiltration. All inoculated transgenic mice died by day 6. Inoculated wild-type mice remained healthy. Dexamethasone attenuated clinical and histopathological ALI evidence in transgenic mice. This study confirms the translational validity of a pseudovirus-based approach, providing a robust and accessible platform to assess ALI pathophysiology and evaluate candidate therapies.