A sialylated voltage-dependent Ca2+ channel binds hemagglutinin and mediates influenza a virus entry into mammalian cells

Summary Influenza A virus (IAV) infection is initiated by the attachment of the viral glycoprotein hemagglutinin (HA) to sialic acid on the host cell surface. However, the sialic acid-containing receptor crucial for IAV infection has remained unidentified. Here, we show that HA binds to the voltage-dependent Ca 2+ channel Ca v 1.2 to trigger intracellular Ca 2+ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by Ca 2+ channel blockers (CCBs) or by knockdown of Ca v 1.2. The CCB diltiazem also inhibited virus replication in vivo . Reintroduction of wild-type but not the glycosylation-deficient mutants of Ca v 1.2 restored Ca 2+ oscillations and virus infection in Ca v 1.2-depleted cells, demonstrating the significance of Ca v 1.2 sialylation. Taken together, we identify Ca v 1.2 as a sialylated host cell surface receptor that binds HA and is critical for IAV entry.