MDA-5 recognition of a murine norovirus.
MDA-5 recognition of a murine norovirus.
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DOI：
10.1371/journal.ppat.1000108
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发表时间：
2008-07-18
期刊：
影响因子：
6.7
通讯作者：
Colonna M
中科院分区：
文献类型：
--
作者：
McCartney SA;Thackray LB;Gitlin L;Gilfillan S;Virgin HW;Colonna M
诺如病毒是重要的人类病原体，是造成全球大多数病毒性流行性胃肠炎病例的原因。鼠诺如病毒-1 (MNV-1) 是从研究小鼠设施中分离出的几种鼠诺如病毒之一，已被用作人类诺如病毒感染的模型。 MNV-1 感染已被证明需要先天性和适应性免疫的成分才能清除；然而，识别 MNV-1 感染的初始宿主蛋白尚不清楚。由于诺如病毒是 RNA 病毒，我们研究了识别 dsRNA 的细胞传感器 MDA5 和 TLR3 对于宿主对 MNV-1 的反应是否重要。我们证明 MDA5−/− 树突状细胞 (DC) 对 MNV-1 的细胞因子反应存在缺陷。此外，MNV-1 在 MDA5−/− DC 以及 MDA5−/− 小鼠体内复制到更高水平。有趣的是，TLR3−/− DCs 在体外没有缺陷，但 TLR3−/− 小鼠的病毒滴度略有增加。这是诺如病毒先天免疫传感器的首次演示，并表明 MDA5 是控制 MNV-1 感染所必需的。了解宿主对 MNV-1 的反应可能为预防和治疗人类疾病提供关键。胃肠炎是发达国家和发展中国家的常见疾病。造成这种痛苦的两个主要原因是细菌和病毒。与胃肠炎有关的主要病毒已被证明是诺如病毒，其中包括诺瓦克病毒，该病毒因最近在游轮上多次爆发而臭名昭著。我们感兴趣的是先天免疫系统如何检测病毒感染并让宿主做好应对威胁的准备。为了了解宿主如何响应诺如病毒感染，我们研究了两类蛋白质，这两种蛋白质都被认为可以检测病毒感染的迹象。我们发现其中一种蛋白质，黑色素瘤分化相关蛋白 5 (MDA-5)，负责检测与人类病原体遗传相关的小鼠诺如病毒。这些发现使我们能够更好地了解诺如病毒感染的发病机制，并可能为控制人类疾病提供线索。
Noroviruses are important human pathogens responsible for most cases of viral epidemic gastroenteritis worldwide. Murine norovirus-1 (MNV-1) is one of several murine noroviruses isolated from research mouse facilities and has been used as a model of human norovirus infection. MNV-1 infection has been shown to require components of innate and adaptive immunity for clearance; however, the initial host protein that recognizes MNV-1 infection is unknown. Because noroviruses are RNA viruses, we investigated whether MDA5 and TLR3, cellular sensors that recognize dsRNA, are important for the host response to MNV-1. We demonstrate that MDA5−/− dendritic cells(DC) have a defect in cytokine response to MNV-1. In addition, MNV-1 replicates to higher levels in MDA5−/− DCs as well as in MDA5−/− mice in vivo. Interestingly, TLR3−/− DCs do not have a defect in vitro, but TLR3−/− mice have a slight increase in viral titers. This is the first demonstration of an innate immune sensor for norovirus and shows that MDA5 is required for the control of MNV-1 infection. Knowledge of the host response to MNV-1 may provide keys for prevention and treatment of the human disease. Gastroenteritis is a common disease in both developed and developing countries. The two main causes of this affliction are bacteria and viruses. The primary viruses implicated in gastroenteritis have been shown to be noroviruses, which include Norwalk virus, notorious for numerous recent outbreaks on cruise ships. We are interested in how the innate immune system detects viral infection and prepares the host to respond to the threat. To understand how the host responds to norovirus infection, we studied two classes of proteins, both of which are thought to detect signs of viral infection. We discovered that one of these proteins, melanoma differentiation associated protein-5 (MDA-5), is responsible for detecting a mouse norovirus that is genetically related to the human pathogen. These findings allow us to better understand the pathogenesis of norovirus infection and may provide clues for controlling the human disease.
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