title: Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors.
abstract: Upon activation by the ligands Gas6 and Protein S, Tyro3/Axl/Mer (TAM) receptor tyrosine kinases promote phagocytic clearance of apoptotic cells and downregulate immune responses initiated by Toll-like receptors and type I interferons (IFNs). Many enveloped viruses display the phospholipid phosphatidylserine on their membranes, through which they bind Gas6 and Protein S and engage TAM receptors. We find that ligand-coated viruses activate TAM receptors on dendritic cells (DCs), dampen type I IFN signaling, and thereby evade host immunity and promote infection. Upon virus challenge, TAM-deficient DCs display type I IFN responses that are elevated in comparison to wild-type cells. As a consequence, TAM-deficient DCs are relatively resistant to infection by flaviviruses and pseudotyped retroviruses, but infection can be restored with neutralizing type I IFN antibodies. Correspondingly, a TAM kinase inhibitor antagonizes the infection of wild-type DCs. Thus, TAM receptors are engaged by viruses in order to attenuate type I IFN signaling and represent potential therapeutic targets.
authors: Nomis Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Suchita
authors: S
authors: Bhattacharyya
authors: Anna
authors: A
authors: Zagórska
authors: Erin D
authors: ED
authors: Lew
authors: Bimmi
authors: B
authors: Shrestha
authors: Carla V
authors: CV
authors: Rothlin
authors: John
authors: J
authors: Naughton
authors: Michael S
authors: MS
authors: Diamond
authors: Greg
authors: G
authors: Lemke
authors: John A T
authors: JA
authors: Young
mesh_terms: D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology*; D005416:Flavivirus / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D007370:Interferon Type I / Q000096:biosynthesis; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000276:immunology*; D015398:Signal Transduction; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D007370:Interferon Type I; D011518:Proto-Oncogene Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
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