title: 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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Miner
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Daniels
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Bimmi
authors.initials: B
authors.lastname: Shrestha
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.|Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Proenca-Modena
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California, USA.
authors.forename: Erin D
authors.initials: ED
authors.lastname: Lew
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.|Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Lazear
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gorman
authors.affiliation: Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, California, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.|Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, Missouri, USA.|Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
authors.affiliation: Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA.|Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.|Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri, USA.|The Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D018925:Chemokines / Q000097:blood; D004670:Encephalitis, California / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D016899:Interferon-beta / Q000378:metabolism; D018062:La Crosse virus / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology; D010539:Permeability; D020011:Protective Agents; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D011836:Radiation Tolerance; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D019562:Viral Load; D014901:West Nile Fever / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D014902:West Nile virus / Q000502:physiology; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D018925:Chemokines; D020011:Protective Agents; D011518:Proto-Oncogene Proteins; D016899:Interferon-beta; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase