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.

肿瘤坏死因子相关凋亡诱导配体（TRAIL）死亡受体（DR）可调控细胞凋亡与炎症反应，但其在抗病毒防御中的作用尚不明晰。巨细胞病毒（CMV）编码多种可重塑宿主免疫的免疫调控基因，并通过多种策略靶向肿瘤坏死因子家族细胞因子。本研究证实，小鼠巨细胞病毒（MCMV）的m166开放阅读框（orf）是抑制感染细胞中TRAIL-DR表达所严格必需的元件。缺失m166表达的MCMV突变株（m166stop）在体内的复制能力严重受损，尤以肝脏最为显著；清除自然杀伤（NK）细胞或使用TRAIL-DR基因敲除（TRAIL-DR−/−）小鼠，均可完全恢复MCMV-m166stop的复制能力。上述结果凸显：巨细胞病毒演化出抑制TRAIL-DR信号通路的策略以抵御NK细胞介导的免疫防御，这一机制对其存活至关重要。