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

Cell Host Microbe. 2018 Jun 13;23(6):809-818.e5. doi: 10.1016/j.chom.2018.04.015. Epub 2018 May 17.

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 Cav1.2 to trigger intracellular Ca2+ oscillations and subsequent IAV entry and replication. IAV entry was inhibited by Ca2+ channel blockers (CCBs) or by knockdown of Cav1.2. The CCB diltiazem also inhibited virus replication in vivo. Reintroduction of wild-type but not the glycosylation-deficient mutants of Cav1.2 restored Ca2+ oscillations and virus infection in Cav1.2-depleted cells, demonstrating the significance of Cav1.2 sialylation. Taken together, we identify Cav1.2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • COS Cells
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Chlorocebus aethiops
  • Dogs
  • HEK293 Cells
  • HeLa Cells
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism*
  • Humans
  • Influenza A virus / physiology*
  • Influenza, Human / pathology
  • Influenza, Human / virology*
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology*

Substances

  • CACNA1C protein, human
  • CACNA1C protein, mouse
  • Calcium Channels, L-Type
  • Hemagglutinin Glycoproteins, Influenza Virus