Enveloped Viruses Disable Innate Immune Responses in Dendritic Cells by Direct Activation of TAM Receptors

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 phosphati...

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Published inCell host & microbe Vol. 14; no. 2; pp. 136 - 147
Main Authors Bhattacharyya, Suchita, Zagórska, Anna, Lew, Erin D., Shrestha, Bimmi, Rothlin, Carla V., Naughton, John, Diamond, Michael S., Lemke, Greg, Young, John A.T.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 14.08.2013
Subjects
Animals
c-Mer Tyrosine Kinase
Cell Line
Dendritic Cells - immunology
Flavivirus - immunology
Humans
Immune Tolerance
Immunity, Innate
Interferon Type I - biosynthesis
Mice
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Receptor Protein-Tyrosine Kinases - genetics
Receptor Protein-Tyrosine Kinases - metabolism
Retroviridae - immunology
Signal Transduction
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Summary: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. •Enveloped viruses bind TAM receptor ligands via phosphatidylserine•Viruses strongly activate TAM receptors in DCs•Activated TAM receptors inhibit IFN signaling•Pharmacological inhibition of TAM receptors inhibits virus replication
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These authors contributed equally to this work
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2013.07.005