A Sialylated Voltage-Dependent Ca2+ Channel Binds Hemagglutinin and Mediates Influenza A Virus Entry into Mammalian Cells

Abstract

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 Ca_v1.2 to trigger intracellular Ca²⁺ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by Ca²⁺ channel blockers (CCBs) or by knockdown of Ca_v1.2. The CCB diltiazem also inhibited virus replication in vivo. Reintroduction of wild-type but not the glycosylation-deficient mutants of Ca_v1.2 restored Ca²⁺ oscillations and virus infection in Ca_v1.2-depleted cells, demonstrating the significance of Ca_v1.2 sialylation. Taken together, we identify Ca_v1.2 as a sialylated host cell surface receptor that binds HA and is critical for IAV entry.

Keywords: calcium channel; calcium channel blockers; calcium ion; hemagglutinin; influenza A virus; sialylation; virus entry; virus-host cell interaction.