Lupus acceleration by a MAVS-activating RNA virus requires endosomal TLR signaling and host genetic predisposition
Lupus acceleration by a MAVS-activating RNA virus requires endosomal TLR signaling and host genetic predisposition
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DOI：
10.1371/journal.pone.0203118
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发表时间：
2018-09-10
期刊：
影响因子：
3.7
通讯作者：
Baccala, Roberto
中科院分区：
文献类型：
--
作者：
Gonzalez-Quintial, Rosana;Nguyen, Anthony;Baccala, Roberto
长期以来，病毒一直与自身免疫性疾病的发病机制有关，但它们的作用仍然是间接的，部分原因是缺乏关于自身免疫性疾病发作前感染的充分记录的信息。在这里，我们使用淋巴细胞性脉络丛脑膜炎病毒（LCMV）作为一个模型，机械解剖病毒感染对狼疮样自身免疫的影响。病毒持久性强烈增强疾病的小鼠，否则弱的遗传易感性，但不是在高度易感或非自身免疫性小鼠，表明遗传易感性和病毒感染之间的协同作用。此外，内体Toll样受体（TLR）和浆细胞样树突状细胞（pDC）都是疾病加速所严格需要的，即使LCMV也通过RNA解旋酶和MAVS在常规DC中诱导强烈的TLR非依赖性I型干扰素（IFN-I）产生。这些结果表明，LCMV增强全身性自身免疫主要是通过提供刺激性核酸的内体TLR参与，而过度刺激的MAVS依赖性胞质途径的内体TLR信号转导的情况下是不足以诱导疾病。
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.