急性病毒感染加速渐冻人症小鼠模型的神经退行性变

Art Marzok, Jonathan P Mapletoft, Braeden Cowbrough, Daniel B Celeste, Michael R D'Agostino, Jann C Ang, Andrew Chen, Vithushan Surendran, Anna Dvorkin-Gheva, Ali Zhang, Yasmine Kollar, Hannah D Stacey, Sam Afkhami, Mannie Lam, Kevin R Milnes, Matthew S Miller
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引用次数: 0

摘要

虽然有几种病毒感染与肌萎缩性脊髓侧索硬化症(ALS)有关,但它们促进疾病发生的机制却几乎完全不为人知。本研究在 SOD1G93A 小鼠模型中研究了发病前常见急性病毒感染对 ALS 进展的影响。在渐冻症临床症状出现之前的一次亚致死性感染会明显加速渐冻症的进展,其特点是后肢功能迅速丧失。之前的感染会导致腰椎神经胶质增生,并上调涉及炎症反应、代谢失调和肌肉功能障碍的转录通路。用抗炎小分子或直接作用抗病毒药物治疗抑制神经胶质增生与明显改善 ALS 临床症状有关,这与在未感染动物身上观察到的情况类似。这项研究提供了因果关系和机理方面的证据,证明急性病毒感染引起的免疫反应可能是改变 ALS 疾病轨迹的重要病因,并为 ALS 的新型治疗和预防策略提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Acute Viral Infection Accelerates Neurodegeneration in a Mouse Model of ALS
While several viral infections have been associated with amyotrophic lateral sclerosis (ALS), the mechanism(s) through which they promote disease has remained almost entirely elusive. This study investigated the impact of common, acute viral infections prior to disease onset on ALS progression in the SOD1G93A mouse model. A single sublethal infection prior to onset of ALS clinical signs was associated with markedly accelerated ALS disease progression characterized by rapid loss of hindlimb function. Prior infection resulted in gliosis in the lumbar spine and upregulation of transcriptional pathways involved in inflammatory responses, metabolic dysregulation, and muscular dysfunction. Therapeutic suppression of gliosis with an anti-inflammatory small molecule, or administration of a direct-acting antiviral, was associated with significantly improved ALS clinical signs, akin to what was observed in uninfected animals. This study provides causal and mechanistic evidence that the immune response elicited by acute viral infections may be an important etiological factor that alters ALS disease trajectory, and provides insight into novel therapeutic and preventative strategies for ALS.
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