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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.

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Figure 1: Mortality and viral burden in WT and TAM receptor-deficient mice after subcutaneous or intracranial infection with WNV.
Figure 2: BBB permeability in WT and TAM receptor–deficient mice.
Figure 3: Vulnerability, viral burden and BBB permeability in WT, Axl−/− and Mertk−/− mice after infection with LACV.
Figure 4: Analysis of barrier integrity in brain microvascular endothelial cells from Axl−/−Mertk−/− mice.
Figure 5: Mertk signaling tightens BMEC barriers and functions synergistically with IFN-β.
Figure 6: Enhanced BBB permeability occurs independently of Mertk expression on astrocytes and radio-sensitive cells.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants U19 AI083019 (M.S.D. and R.S.K.), R01 AI101400 (M.S.D. and G.L.), R01 NS052632 (R.S.K.) and R01 NS085296 (G.L.). J.J.M. was supported by an NIH training grant (T32-AR007279) and a Rheumatology Research Foundation Scientist Development Award. B.P.D. was supported by a National Science Foundation Graduate Research Fellowship (DGE-1143954) and an NIH predoctoral fellowship (F31-NS07866). E.D.L. was supported by postdoctoral fellowships from the Leukemia and Lymphoma Society and the Nomis Foundation. We thank A. Pekosz (Johns Hopkins University) for the original LACV strain.

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J.J.M., B.P.D., H.M.L., G.L., R.S.K. and M.S.D. designed the experiments; J.J.M., B.P.D., B.S., J.L.P.-M., H.M.L. and M.J.G. performed the experiments; E.D.L. and G.L. contributed essential reagents; and J.J.M. and M.S.D. wrote the initial draft of the manuscript, with all other authors providing critical comments and editorial changes.

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Correspondence to Michael S Diamond.

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Miner, J., Daniels, B., Shrestha, B. et al. The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. Nat Med 21, 1464–1472 (2015). https://doi.org/10.1038/nm.3974

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