STING is required for host defense against neuropathological West Nile virus infection
STING is required for host defense against neuropathological West Nile virus infection
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DOI：
10.1371/journal.ppat.1007899
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发表时间：
2019-08
期刊：
影响因子：
6.7
通讯作者：
Kathryn McGuckin Wuertz;P. Treuting;Emily A. Hemann;K. Esser-Nobis;Annelise G. Snyder;Jessica B. Graham;B. Daniels;C. Wilkins;J. Snyder;Kathleen M. Voss;A. Oberst;Jennifer M. Lund;M. Gale
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文献类型：
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作者：
Kathryn McGuckin Wuertz;P. Treuting;Emily A. Hemann;K. Esser-Nobis;Annelise G. Snyder;Jessica B. Graham;B. Daniels;C. Wilkins;J. Snyder;Kathleen M. Voss;A. Oberst;Jennifer M. Lund;M. Gale
西尼罗河病毒(West Nile Virus，WNV)是一种新出现和重新出现的RNA病毒，是美国虫媒病毒性脑炎发病率和死亡率的主要来源。西尼罗河病毒的感染受到中枢神经系统(CNS)外的外周组织天然免疫的强烈控制，但WNV可以逃避干扰素(IFN)的作用，促进中枢神经系统的入侵，导致脑炎、脑脊髓炎和死亡。最近的研究表明，干扰素基因刺激物(STINT)是宿主抵御嗜神经RNA病毒所必需的，它能启动I型干扰素的产生和对胞浆DNA的天然免疫反应。我们在一种小鼠感染模型中评估了刺痛在宿主防御中控制西尼罗河病毒感染和病理的作用。与野生型(WT)小鼠相比，当受到西尼罗河病毒攻击时，叮击敲除(-/-)小鼠的发病率和死亡率更高。病毒学分析和对STING激活的评估表明，在脾中控制WNV不需要STING信号，WNV也不足以在体外介导典型的STING激活。然而，被叮咬的小鼠表现出明显的病毒载量增加和病毒在中枢神经系统传播的趋势。我们发现，与WT小鼠相比，被叮咬的小鼠表现出更多和更长的神经体征。病理检查发现，病毒清除后小鼠中枢神经系统病变增多，单核细胞浸润，神经元死亡，并持续病理改变。我们发现，骨髓来源的巨噬细胞需要刺痛来早期控制西尼罗河病毒的复制和天然免疫激活。在体内，与WT小鼠相比，在WNV感染期间，刺痛/-小鼠在脾和脑中都产生了异常的T细胞反应，这与增加和持续的中枢神经系统病理有关。我们的发现表明，在控制嗜神经性西尼罗河病毒感染和中枢神经系统疾病的免疫程序中，STING起着关键作用。
West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.