Lupus acceleration by a MAVS-activating RNA virus requires endosomal TLR signaling and host genetic predisposition

Viruses have long been implicated in the pathogenesis of autoimmunity, yet their contribution remains circumstantial partly due to the lack of well-documented information on infections prior to autoimmune disease onset. Here, we used the lymphocytic choriomeningitis virus (LCMV) as a model to mechanistically dissect the impact of viral infection on lupus-like autoimmunity. Virus persistence strongly enhanced disease in mice with otherwise weak genetic predisposition but not in highly predisposed or non-autoimmune mice, indicating a synergistic interplay between genetic susceptibility and virus infection. Moreover, endosomal Toll-like receptors (TLRs) and plasmacytoid dendritic cells (pDCs) were both strictly required for disease acceleration, even though LCMV also induces strong TLR-independent type I interferon (IFN-I) production via RNA helicases and MAVS in conventional DCs. These results suggest that LCMV enhances systemic autoimmunity primarily by providing stimulatory nucleic acids for endosomal TLR engagement, whereas overstimulation of the MAVS-dependent cytosolic pathway in the absence of endosomal TLR signaling is insufficient for disease induction.长期以来，病毒一直被认为与自身免疫的发病机制密切相关，但其具体贡献仍仅为间接证据，部分原因在于自身免疫疾病发作前缺乏关于感染的详实记录。本研究以淋巴性脉络丛脑膜炎病毒（lymphocytic choriomeningitis virus, LCMV）为模型，从机制层面深入解析病毒感染对狼疮样自身免疫的影响。在原本遗传易感程度较弱的小鼠中，病毒持续感染显著加重了疾病表型，但在高度易感或非自身免疫易感小鼠中并未观察到该效果，这表明遗传易感性与病毒感染之间存在协同交互作用。此外，尽管LCMV还可通过常规树突状细胞中的RNA解旋酶（RNA helicases）与线粒体抗病毒信号蛋白（MAVS）诱导不依赖Toll样受体的强效I型干扰素（type I interferon, IFN-I）产生，但内体Toll样受体（endosomal Toll-like receptors, TLRs）与浆细胞样树突状细胞（plasmacytoid dendritic cells, pDCs）均是疾病加速进程所严格必需的。上述结果表明，LCMV主要通过为内体Toll样受体的结合提供刺激性核酸来增强全身性自身免疫，而在缺乏内体Toll样受体信号传导的情况下，过度激活MAVS依赖的胞质通路并不足以诱导疾病发生。