Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses

Cell Rep. 2017 Jan 10;18(2):324-333. doi: 10.1016/j.celrep.2016.12.045.

Abstract

ZIKA virus (ZIKV) is an emerging pathogen responsible for neurological disorders and congenital microcephaly. However, the molecular basis for ZIKV neurotropism remains poorly understood. Here, we show that Axl is expressed in human microglia and astrocytes in the developing brain and that it mediates ZIKV infection of glial cells. Axl-mediated ZIKV entry requires the Axl ligand Gas6, which bridges ZIKV particles to glial cells. Following binding, ZIKV is internalized through clathrin-mediated endocytosis and traffics to Rab5+ endosomes to establish productive infection. During entry, the ZIKV/Gas6 complex activates Axl kinase activity, which downmodulates interferon signaling and facilitates infection. ZIKV infection of human glial cells is inhibited by MYD1, an engineered Axl decoy receptor, and by the Axl kinase inhibitor R428. Our results highlight the dual role of Axl during ZIKV infection of glial cells: promoting viral entry and modulating innate immune responses. Therefore, inhibiting Axl function may represent a potential target for future antiviral therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / embryology
  • Brain / metabolism
  • Clathrin / metabolism
  • Endocytosis
  • Endosomes / metabolism
  • Humans
  • Immunity, Innate*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interferon Type I / metabolism
  • Neuroglia / metabolism*
  • Neuroglia / pathology
  • Neuroglia / virology*
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Virus Internalization*
  • Zika Virus / physiology*
  • Zika Virus Infection / pathology
  • Zika Virus Infection / virology

Substances

  • Clathrin
  • Intercellular Signaling Peptides and Proteins
  • Interferon Type I
  • Proto-Oncogene Proteins
  • growth arrest-specific protein 6
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase