TY - JOUR
T1 - Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors
AU - Bhattacharyya, Suchita
AU - Zagórska, Anna
AU - Lew, Erin D.
AU - Shrestha, Bimmi
AU - Rothlin, Carla V.
AU - Naughton, John
AU - Diamond, Michael S.
AU - Lemke, Greg
AU - Young, John A.T.
N1 - Funding Information:
We thank C. Powers and C. O’Shea (the Salk Institute) for providing the purified MAV-1 virus stock and S. Buhrlage and N. Gray at Harvard Medical School for alerting us to BMS-777607 and for sharing other candidate TAM receptor antagonists with us. We also thank members of the Young and Lemke labs and the Nomis Center for helpful discussions. This research was supported by grants from the National Institutes of Health (PO1 AI090935 and UO1 AI074539 to J.A.T.Y.; R01 AI077058 and R01 AI101400 to G.L.; R01 R01AI089824 to C.V.R., U54 AI081680 to M.S.D., and P30 CA014195-38 to the Salk Institute), the Nomis and Auen Foundations, the James B. Pendleton Charitable Trust (to J.A.T.Y.), a Salk Institute innovation grant (to G.L. and J.A.T.Y.), and postdoctoral fellowships from the Human Frontiers Science Program (to A.Z.) and the Leukemia and Lymphoma Society and Nomis Foundation (to E.D.L.).
PY - 2013/8/14
Y1 - 2013/8/14
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84882338751
U2 - 10.1016/j.chom.2013.07.005
DO - 10.1016/j.chom.2013.07.005
M3 - Article
C2 - 23954153
AN - SCOPUS:84882338751
SN - 1931-3128
VL - 14
SP - 136
EP - 147
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 2
ER -