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.Author summary: The SARS-CoV-2 that causes coronavirus disease 2019 (COVID-19), including its Delta and Omicron BA.5 variants, replicates efficiently at core body temperature of 37°C. Here we demonstrated that the thermo-sensitive cation channel TRPV4, which is activated at this temperature, plays a key role in the SARS-CoV-2 replication. Blocking the TRPV4 signals with certain drugs—like cyclosporine A or manidipine, a medication already approved for blood pressure treatment—reduced the SARS-CoV-2 replication in vitro and in vivo. These drugs also protected Syrian hamsters from lethal SARS-CoV-2 Delta variant infection. Our finding suggests that manidipine could be repurposed as a treatment for COVID-19, offering a potential new tool to fight the disease.