TRPV4-mediated calcium influx contributes temperature-dependent SARS-CoV-2 replication

Temperature varies across the nasal cavity, lower respiratory tract, and during febrile conditions, yet the impact of these differences on SARS-CoV-2 replication remains poorly understood. Here, we show that ancestral SARS-CoV-2, Delta, or Omicron BA.5 variants replicate most efficiently at 37°C. We found that transient receptor potential vanilloid 4 (TRPV4)-mediated calcium influx, a thermosensitive cation channel known to be activated at 37°C, contributes to efficient SARS-CoV-2 replication. In addition, a calcineurin inhibitor, cyclosporine A (Cys A), and manidipine, an FDA-approved calcium channel blocker, both suppressed viral replication and protected Syrian hamsters from lethal infection with the SARS-CoV-2 Delta variant. Notably, a selective TRPV4 antagonist also conferred protection in infected hamsters. These results suggest that TRPV4-mediated calcium influx contributes to efficient SARS-CoV-2 replication at 37°C and highlight manidipine as a strong candidate for repurposing as an anti-SARS-CoV-2 therapeutic.