Inhibition of the TRAIL Death Receptor by CMV Reveals Its Importance in NK Cell-Mediated Antiviral Defense |
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| Authors: | Shilpi Verma Andrea Loewendorf Qiao Wang Bryan McDonald Alec Redwood Chris A Benedict |
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| Institution: | 1. Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America.; 2. Microbiology and Immunology, School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.; University of California, Berkeley, United States of America, |
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| Abstract: | TNF-related apoptosis inducing ligand (TRAIL) death receptors (DR) regulate apoptosis and inflammation, but their role in antiviral defense is poorly understood. Cytomegaloviruses (CMV) encode many immune-modulatory genes that shape host immunity, and they utilize multiple strategies to target the TNF-family cytokines. Here we show that the m166 open reading frame (orf) of mouse CMV (MCMV) is strictly required to inhibit expression of TRAIL-DR in infected cells. An MCMV mutant lacking m166 expression (m166stop) is severely compromised for replication in vivo, most notably in the liver, and depleting natural killer (NK) cells, or infecting TRAIL-DR−/− mice, restored MCMV-m166stop replication completely. These results highlight the critical importance for CMV to have evolved a strategy to inhibit TRAIL-DR signaling to thwart NK-mediated defenses. |
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