IL-1β signaling promotes CNS-intrinsic immune control of West Nile virus infection.
IL-1β signaling promotes CNS-intrinsic immune control of West Nile virus infection.
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DOI：
10.1371/journal.ppat.1003039
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Gale M Jr
中科院分区：
文献类型：
--
作者：
Ramos HJ;Lanteri MC;Blahnik G;Negash A;Suthar MS;Brassil MM;Sodhi K;Treuting PM;Busch MP;Norris PJ;Gale M Jr
西尼罗河病毒（West Nile virus，WNV）是一种新发现的黄病毒，能感染中枢神经系统，引起神经细胞死亡和组织破坏。在CNS内促进炎症和脑炎的过程对于控制WNV疾病是重要的，但是，炎症信号传导途径如何操作以控制CNS感染尚未确定。在这里，我们确定IL-1β信号传导和NLRP 3炎性体是参与病毒控制和与WNV感染相关的CNS疾病的关键宿主限制因子。急性西尼罗河病毒感染的个体在感染过程中血浆中IL-1β水平升高，表明IL-1β在西尼罗河病毒免疫中的作用。事实上，我们发现在感染的小鼠模型中，WNV诱导体内IL-1β的急性产生，并且缺乏IL-1受体或参与炎性体信号传导复合物的组分的动物表现出对WNV发病机制的易感性增加。该结果与CNS内而非外周组织内病毒蓄积增加相关，并进一步与炎症动力学和程度改变、效应CD 8 + T细胞应答质量降低和CNS内抗病毒活性降低相关。重要的是，我们发现WNV感染触发皮质神经元产生IL-1β。此外，我们发现IL-1β信号传导与I型IFN协同抑制神经元中的WNV复制，从而暗示IL-1β在神经元内的抗病毒活性和CNS内病毒复制的控制。因此，我们的研究将NLRP 3炎性体途径和IL-1β信号传导定义为控制CNS中WNV感染和免疫的关键特征，并揭示了IL-1β在限制病毒在神经元中复制的抗病毒作用中的新作用。自1999年引入北美以来，西尼罗河病毒（WNV）已成为美国病毒性脑炎疾病的主要原因。虽然低水平的炎症对于WNV的清除很重要，但高水平的炎症与疾病增加有关。本研究的目的是确定控制炎症平衡和对西尼罗河病毒的保护性免疫的宿主信号通路。使用感染的小鼠模型，我们鉴定了中枢神经系统（CNS）对NLRP 3炎性体和IL-1β信号传导的内在需求，以限制CNS内的WNV相关疾病。首先，IL-1β信号传导对于调节CNS内炎症的程度和动力学是必不可少的。其次，IL-1β信号的缺乏破坏了效应T淋巴细胞针对病毒的反应质量。最后，这些失调的免疫应答与IL-1β信号传导与I型IFN信号传导协同作用并限制皮质神经元（CNS内WNV感染的关键靶细胞）内病毒复制的直接能力有关。这项研究将NLRP 3炎性体和IL-1β信号转导共同确定为关键限制因子，其作用是调节CNS内的病毒载量和炎症反应的质量，以赋予针对WNV感染的保护性免疫。
West Nile virus (WNV) is an emerging flavivirus capable of infecting the central nervous system (CNS) and mediating neuronal cell death and tissue destruction. The processes that promote inflammation and encephalitis within the CNS are important for control of WNV disease but, how inflammatory signaling pathways operate to control CNS infection is not defined. Here, we identify IL-1β signaling and the NLRP3 inflammasome as key host restriction factors involved in viral control and CNS disease associated with WNV infection. Individuals presenting with acute WNV infection displayed elevated levels of IL-1β in their plasma over the course of infection, suggesting a role for IL-1β in WNV immunity. Indeed, we found that in a mouse model of infection, WNV induced the acute production of IL-1β in vivo, and that animals lacking the IL-1 receptor or components involved in inflammasome signaling complex exhibited increased susceptibility to WNV pathogenesis. This outcome associated with increased accumulation of virus within the CNS but not peripheral tissues and was further associated with altered kinetics and magnitude of inflammation, reduced quality of the effector CD8+ T cell response and reduced anti-viral activity within the CNS. Importantly, we found that WNV infection triggers production of IL-1β from cortical neurons. Furthermore, we found that IL-1β signaling synergizes with type I IFN to suppress WNV replication in neurons, thus implicating antiviral activity of IL-1β within neurons and control of virus replication within the CNS. Our studies thus define the NLRP3 inflammasome pathway and IL-1β signaling as key features controlling WNV infection and immunity in the CNS, and reveal a novel role for IL-1β in antiviral action that restricts virus replication in neurons. Since its introduction into North America in 1999, West Nile virus (WNV) has emerged as a leading cause of viral encephalitic disease in the United States. While low level inflammation is important for clearance of WNV, high levels of inflammation are associated with increased disease. The goal of this study was to identify host signaling pathways that control the balance of inflammation and protective immunity to WNV. Using a mouse model of infection, we identified a central nervous system (CNS)-intrinsic requirement for the NLRP3 inflammasome and IL-1β signaling in limiting WNV associated disease within the CNS. First, IL-1β signaling was essential for regulating the magnitude and kinetics of inflammation within CNS. Secondly, the absence of IL-1β signaling disrupted the quality of the effector T lymphocyte response against the virus. Finally, these dysregulated immune responses were linked to a direct ability for IL-1β signaling to synergize with type I IFN signaling and limit virus replication within cortical neurons, key target cells of WNV infection within the CNS. Together this study identifies the NLRP3 inflammasome and IL-1β signaling as key restriction factors that act to regulate viral load and the quality of inflammatory responses within the CNS to impart protective immunity against WNV infection.
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影响因子：
6.4
作者：
CHANG, DM;SHAIO, MF
通讯作者：
SHAIO, MF
DOI：
10.1038/nri2851
发表时间：
2010-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.8
作者：
Hayes EB;Komar N;Nasci RS;Montgomery SP;O'Leary DR;Campbell GL
通讯作者：
Campbell GL
影响因子：
30.5
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
通讯作者：
Superti-Furga, Giulio
影响因子：
11.8
作者：
Gubler, Duane J.
通讯作者：
Gubler, Duane J.