The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection
The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection
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DOI：
10.1128/jvi.01488-13
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发表时间：
2013-11-01
影响因子：
5.4
通讯作者：
Gale, Michael, Jr.
中科院分区：
文献类型：
--
作者：
Errett, John S.;Suthar, Mehul S.;Gale, Michael, Jr.
先天免疫系统对病毒的识别和应答是宿主防御感染的关键组成部分。针对西尼罗河病毒（WNV）（一种新兴的载体传播病毒）的细胞固有免疫的激活和适应性免疫的最佳引发依赖于RIG-I和MDA 5的识别，RIG-I和MDA 5是RIG-I样受体（RLR）蛋白家族的两种胞质模式识别受体（PRR），其识别病毒RNA并激活抑制感染的防御程序。我们评估了RIG-I和MDA 5在体外和体内的病原体识别和控制西尼罗河病毒中的各自功能。单独缺乏RIG-I或MDA 5导致体外原代细胞中先天免疫信号传导和病毒控制降低，并增加小鼠的死亡率。我们还产生了RIG-I-/- x MDA 5（-/-）双敲除小鼠，并发现两种RLR的缺乏导致WNV感染的靶细胞中完全不存在先天免疫基因诱导和体内感染期间的严重发病机制，与缺乏MAVS（RLR信号传导的中心衔接分子）的动物的发现相似。我们还发现，来自WNV感染的细胞的RNA产物而不是进入的病毒体RNA显示至少两种不同的病原体相关分子模式（PAMP），其含有在感染期间暂时分布并由RIG-I和MDA 5感测的5'三磷酸和双链RNA。因此，RIG-I和MDA 5是识别在WNV复制期间积累的不同PAMP的必需PRR。总的来说，这些实验强调了多个相关的细胞质宿主传感器在协调针对急性病毒感染的有效免疫应答中的必要性和功能。
Virus recognition and response by the innate immune system are critical components of host defense against infection. Activation of cell-intrinsic immunity and optimal priming of adaptive immunity against West Nile virus (WNV), an emerging vector-borne virus, depend on recognition by RIG-I and MDA5, two cytosolic pattern recognition receptors (PRRs) of the RIG-I-like receptor (RLR) protein family that recognize viral RNA and activate defense programs that suppress infection. We evaluated the individual functions of RIG-I and MDA5 both in vitro and in vivo in pathogen recognition and control of WNV. Lack of RIG-I or MDA5 alone results in decreased innate immune signaling and virus control in primary cells in vitro and increased mortality in mice. We also generated RIG-I-/- x MDA5(-/-) double-knockout mice and found that a lack of both RLRs results in a complete absence of innate immune gene induction in target cells of WNV infection and a severe pathogenesis during infection in vivo, similar to findings for animals lacking MAVS, the central adaptor molecule for RLR signaling. We also found that RNA products from WNV-infected cells but not incoming virion RNA display at least two distinct pathogen-associated molecular patterns (PAMPs) containing 5' triphosphate and double-stranded RNA that are temporally distributed and sensed by RIG-I and MDA5 during infection. Thus, RIG-I and MDA5 are essential PRRs that recognize distinct PAMPs that accumulate during WNV replication. Collectively, these experiments highlight the necessity and function of multiple related, cytoplasmic host sensors in orchestrating an effective immune response against an acute viral infection.