Moe Kobayashi, Hatsumi Abe, Hikaruko Sugihara, Nene Kobayashi, Seira Omori, Yasuhiro Yamada, Takeshi Ichinohe
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.