MyD88-mediated innate immunity against West Nile virus

描述（由申请人提供）：先天免疫是抵抗微生物入侵的第一道防线。Toll样受体（TLR）家族是一组新近定义的先天性免疫受体，在检测保守的微生物组分中起着核心作用。核心TLR信号传导途径利用髓样分化因子88（MyD 88）作为主要衔接子;而其他利用替代衔接子，如TIRAP/Mal、TRIF/TICAM-1和TIRP/TRAM/TICAM-2。在病毒感染时，TLR信号传导的刺激导致NF-κ B的活化和细胞因子（包括抗病毒因子和促炎细胞因子）的释放。TLR信号传导的作用可能对宿主免疫有利和/或潜在有害。我们最近已经证明，西尼罗河（WN）病毒感染小鼠导致TLR 3依赖性炎症反应，参与病毒的脑渗透和神经元损伤，从而导致致命的脑炎。此外，我们在初步研究中发现，MyD 88缺陷（MyD 88-/-）小鼠比野生型小鼠更容易感染WN病毒，这表明MyD 88介导的信号转导参与了针对WN病毒的保护性免疫。TLR 3以不依赖于MyD 88的方式做出反应; TLR 7和8是目前确定的MyD 88依赖性TLR，参与病毒RNA识别。基于这些数据，我们假设MyD 88依赖性TLR 7/8信号传导对于宿主针对WN病毒感染的保护性免疫是重要的。在具体目标1中，我们将进一步检查MyD 88缺陷和TLR 7和8缺陷小鼠中的WN病毒感染。具体目标2是剖析MyD 88介导的先天免疫控制WN病毒感染的效应机制。WN病毒现已引起北美最大规模的病毒性脑炎暴发，并已成为公共卫生问题。这项研究的结果不仅将增强我们对病毒发病机制的理解，还将导致预防和治疗WN脑炎的新策略的发展。

DESCRIPTION (provided by applicant): Innate immunity is the first line of defense against invading microorganisms. The Toll-like receptor (TLR) family, a group of recently defined innate immune receptors, plays a central role in detecting conserved microbial components. The core TLR signaling pathway utilizes myeloid differentiation factor 88 (MyD88) as the primary adaptor; while others utilize alternative adaptors such as TIRAP/Mal, TRIF/TICAM-1 and TIRP/TRAM/TICAM-2. Upon viral infection, stimulation of TLR signaling leads to activation of NF- kB and release of cytokines, including both anti-viral factors and proinflammatory cytokines. The effects of TLR signaling could be favorable and/or potentially detrimental to the host immunity. We have recently demonstrated that West Nile (WN) virus infection in mouse leads to a TLR3-dependent inflammatory response that is involved in both brain penetration of the virus and neuronal injury thereby contributing to lethal encephalitis. Furthermore, we found in the preliminary studies that MyD88 deficient (MyD88-/-) mice were more susceptible to WN virus infection than wild-type mice, suggesting MyD88-mediated signaling is involved in protective immunity against WN virus. TLR3 responds in a MyD88 independent fashion; TLRs 7 and 8 are currently identified MyD88-dependent TLRs that are involved in viral RNA recognition. Based on these data, we hypothesize that MyD88-dependent TLR7/8 signaling is important for host protective immunity against WN virus infection. In Specific aim 1, we will further examine WN virus infection in both MyD88 deficient and TLRs 7 and 8 deficient mice. Specific aim 2 is to dissect the effector mechanisms that underlie MyD88-mediated innate immunity in control of WN virus infection. WN virus has now induced the largest outbreaks of viral encephalitis in North America and has become a public health concern. Results from this study will not only enhance our understanding of the viral pathogenesis; they will also lead to the development of new strategies to prevent and treat WN encephalitis.