Adults older than 65 account for most of the deaths caused by respiratory influenza A virus (IAV) infections, but the underlying mechanisms for this susceptibility are poorly understood. IAV RNA is detected by the cytosolic sensor retinoic acid–inducible gene I (RIG-I), which induces the production of type I interferons (IFNs) that curtail the spread of the virus and promote the elimination of infected cells. We have previously identified a marked defect in the IAV-inducible secretion of type I IFNs, but not proinflammatory cytokines, in monocytes from older (>65 years) healthy human donors. We found that monocytes from older adults exhibited decreased abundance of the adaptor protein TRAF3 (tumor necrosis factor receptor–associated factor 3) because of its increased proteasomal degradation with age, thereby impairing the primary RIG-I signaling pathway for the induction of type I IFNs. We determined that monocytes from older adults also failed to effectively stimulate the production of the IFN regulatory transcription factor IRF8, which compromised IFN induction through secondary RIG-I signaling. IRF8 played a central role in IFN induction in monocytes, because knocking down IRF8 in monocytes from younger adults was sufficient to replicate the IFN defects observed in monocytes from older adults, whereas restoring IRF8 expression in older adult monocytes was sufficient to restore RIG-I–induced IFN responses. Aging thus compromises both the primary and secondary RIG-I signaling pathways that govern expression of type I IFN genes, thereby impairing antiviral resistance to IAV.

65 岁以上的成年人是甲型呼吸道流感病毒 (IAV) 感染造成的死亡的主要原因，但人们对这种易感性的潜在机制知之甚少。 IAV RNA 由胞质传感器视黄酸诱导基因 I (RIG-I) 检测，该基因诱导 I 型干扰素 (IFN) 的产生，从而抑制病毒的传播并促进感染细胞的消除。我们之前已经在老年（>65岁）健康人类捐赠者的单核细胞中发现了IAV诱导的I型干扰素分泌的明显缺陷，但促炎细胞因子却没有。我们发现，老年人的单核细胞表现出接头蛋白 TRAF3（肿瘤坏死因子受体相关因子 3）的丰度下降，因为其蛋白酶体降解随着年龄的增长而增加，从而损害了诱导 I 型干扰素的主要 RIG-I 信号通路。我们确定，来自老年人的单核细胞也未能有效刺激 IFN 调节转录因子 IRF8 的产生，这会通过次级 RIG-I 信号传导损害 IFN 诱导。 IRF8 在单核细胞的 IFN 诱导中发挥着核心作用，因为敲低年轻人单核细胞中的 IRF8 足以复制在老年人单核细胞中观察到的 IFN 缺陷，而恢复老年人单核细胞中的 IRF8 表达足以恢复 RIG-I–诱导干扰素反应。因此，衰老会损害控制 I 型 IFN 基因表达的初级和次级 RIG-I 信号通路，从而损害 IAV 的抗病毒耐药性。