Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors

Suchita Bhattacharyya, Anna Zagórska, Erin D. Lew, Bimmi Shrestha, Carla V. Rothlin, John Naughton, Michael S. Diamond, Greg Lemke, John A.T. Young

Research output: Contribution to journalArticle

111 Scopus citations

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.

Original languageEnglish
Pages (from-to)136-147
Number of pages12
JournalCell Host and Microbe
Volume14
Issue number2
DOIs
StatePublished - Aug 14 2013

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    Bhattacharyya, S., Zagórska, A., Lew, E. D., Shrestha, B., Rothlin, C. V., Naughton, J., Diamond, M. S., Lemke, G., & Young, J. A. T. (2013). Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host and Microbe, 14(2), 136-147. https://doi.org/10.1016/j.chom.2013.07.005