A Sialylated Voltage-Dependent Ca 2+ Channel Binds Hemagglutinin and Mediates Influenza A Virus Entry into Mammalian Cells.

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 Ca2+ channel Cav 1.2 to trigger intracellular Ca2+ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by Ca2+ channel blockers (CCBs) or by knockdown of Cav 1.2. The CCB diltiazem also inhibited virus replication in vivo. Reintroduction of wild-type but not the glycosylation-deficient mutants of Cav 1.2 restored Ca2+ oscillations and virus infection in Cav 1.2-depleted cells, demonstrating the significance of Cav 1.2 sialylation. Taken together, we identify Cav 1.2 as a sialylated host cell surface receptor that binds HA and is critical for IAV entry.