Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 S. 4th Street, Hamilton, MT 59840, USA.
Immunity. 2013 Apr 18;38(4):705-16. doi: 10.1016/j.immuni.2013.02.013. Epub 2013 Mar 14.
La Crosse virus (LACV), a zoonotic Bunyavirus, is a major cause of pediatric viral encephalitis in the United States. A hallmark of neurological diseases caused by LACV and other encephalitic viruses is the induction of neuronal cell death. Innate immune responses have been implicated in neuronal damage, but no mechanism has been elucidated. By using in vitro studies in primary neurons and in vivo studies in mice, we have shown that LACV infection induced the RNA helicase, RIG-I, and mitochondrial antiviral signaling protein (MAVS) signaling pathway, resulting in upregulation of the sterile alpha and TIR-containing motif 1 (SARM1), an adaptor molecule that we found to be directly involved in neuronal damage. SARM1-mediated cell death was associated with induced oxidative stress response and mitochondrial damage. These studies provide an innate-immune signaling mechanism for virus-induced neuronal death and reveal potential targets for development of therapeutics to treat encephalitic viral infections.
拉科罗拉多病毒（LACV）是一种人畜共患的布尼亚病毒，是美国儿童病毒性脑炎的主要病因。由 LACV 和其他脑炎病毒引起的神经疾病的一个标志是诱导神经元细胞死亡。先天免疫反应已被牵连到神经元损伤中，但尚未阐明其机制。通过在原代神经元中的体外研究和在小鼠中的体内研究，我们表明 LACV 感染诱导 RNA 解旋酶 RIG-I 和线粒体抗病毒信号蛋白（MAVS）信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路，导致固有免疫信号通路， sterile alpha 和 TIR-containing motif 1（SARM1）的上调，我们发现 SARM1 是直接参与神经元损伤的衔接分子。SARM1 介导的细胞死亡与诱导的氧化应激反应和线粒体损伤有关。这些研究为病毒诱导的神经元死亡提供了一种先天免疫信号机制，并揭示了开发治疗脑炎病毒感染的治疗方法的潜在靶点。
