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

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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Miner JJ,Daniels BP,Shrestha B,Proenca-Modena JL,Lew ED,Lazear HM,Gorman MJ,Lemke G,Klein RS,Diamond MS

doi

10.1038/nm.3974

subject

Has Abstract

pub_date

2015-12-01 00:00:00

pages

1464-72

issue

12

eissn

1078-8956

issn

1546-170X

pii

nm.3974

journal_volume

21

pub_type

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