Inhibition of the TRAIL Death Receptor by CMV Reveals Its Importance in NK Cell-Mediated Antiviral Defense

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.

TNF相关凋亡诱导配体（TRAIL）死亡受体（DR）调控细胞凋亡和炎症反应，然而其在抗病毒防御中的作用尚不明确。巨细胞病毒（CMV）编码众多免疫调节基因，塑造宿主免疫状态，并采用多种策略靶向TNF家族细胞因子。本研究表明，小鼠CMV（MCMV）中的m166开放阅读框（ORF）对于抑制感染细胞中TRAIL-DR的表达至关重要。缺乏m166表达（m166stop）的MCMV突变体在体内复制能力严重受损，尤其是在肝脏中，而清除自然杀伤（NK）细胞或感染TRAIL-DR−/−小鼠则完全恢复了MCMV-m166stop的复制能力。这些结果凸显了CMV进化出抑制TRAIL-DR信号通路的策略，以挫败NK介导的防御机制的重要性。