The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity

Nat Med. 2015 Dec;21(12):1464-72. doi: 10.1038/nm.3974. Epub 2015 Nov 2.

Abstract

The TAM receptors Tyro3, Axl and Mertk are receptor tyrosine kinases that dampen host innate immune responses following engagement with their ligands Gas6 and Protein S, which recognize phosphatidylserine on apoptotic cells. In a form of apoptotic mimicry, many enveloped viruses display phosphatidylserine on the outer leaflet of their membranes, enabling TAM receptor activation and downregulation of antiviral responses. Accordingly, we hypothesized that a deficiency of TAM receptors would enhance antiviral responses and protect against viral infection. Unexpectedly, mice lacking Mertk and/or Axl, but not Tyro3, exhibited greater vulnerability to infection with neuroinvasive West Nile and La Crosse encephalitis viruses. This phenotype was associated with increased blood-brain barrier permeability, which enhanced virus entry into and infection of the brain. Activation of Mertk synergized with interferon-β to tighten cell junctions and prevent virus transit across brain microvascular endothelial cells. Because TAM receptors restrict pathogenesis of neuroinvasive viruses, these findings have implications for TAM antagonists that are currently in clinical development.

Publication types

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

MeSH terms

  • Adaptive Immunity
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Blood-Brain Barrier / enzymology*
  • Blood-Brain Barrier / pathology
  • Blood-Brain Barrier / virology*
  • Chemokines / blood
  • Encephalitis, California / enzymology*
  • Encephalitis, California / pathology
  • Encephalitis, California / virology
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Interferon-beta / metabolism
  • La Crosse virus / physiology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels / pathology
  • Permeability
  • Protective Agents
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / metabolism*
  • Radiation Tolerance
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / deficiency
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Survival Analysis
  • Viral Load
  • West Nile Fever / enzymology*
  • West Nile Fever / pathology
  • West Nile Fever / virology
  • West Nile virus / physiology
  • c-Mer Tyrosine Kinase

Substances

  • Chemokines
  • Protective Agents
  • Proto-Oncogene Proteins
  • Interferon-beta
  • Mertk protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Tyro3 protein, mouse
  • axl receptor tyrosine kinase
  • c-Mer Tyrosine Kinase