MyD88-mediated innate immunity against West Nile virus

描述（由申请人提供）：先天免疫是抵御入侵微生物的第一道防线。toll样受体（TLR）家族是最近定义的一组先天免疫受体，在检测保守的微生物成分中起着核心作用。核心TLR信号通路利用髓样分化因子88 （MyD88）作为主要适配器；而其他人则使用替代适配器，如TIRAP/Mal， TRIF/TICAM-1和TIRP/TRAM/TICAM-2。病毒感染后，TLR信号的刺激导致NF- kB的激活和细胞因子的释放，包括抗病毒因子和促炎细胞因子。TLR信号的作用可能对宿主免疫有利或潜在有害。我们最近证明，西尼罗河（WN）病毒感染小鼠导致tlr3依赖性炎症反应，该反应涉及病毒的大脑渗透和神经元损伤，从而导致致命性脑炎。此外，我们在初步研究中发现MyD88缺陷小鼠（MyD88-/-）比野生型小鼠更容易受到WN病毒感染，这表明MyD88介导的信号通路参与了对WN病毒的保护性免疫。TLR3以独立于MyD88的方式响应；TLRs 7和8是目前鉴定的myd88依赖性TLRs，参与病毒RNA识别。基于这些数据，我们假设myd88依赖性TLR7/8信号在宿主抗WN病毒感染的保护性免疫中起重要作用。在Specific aim 1中，我们将进一步检查MyD88缺陷小鼠和TLRs 7和8缺陷小鼠的WN病毒感染情况。具体目的2是剖析myd88介导的先天免疫控制WN病毒感染的效应机制。WN病毒现已在北美引发了最大规模的病毒性脑炎暴发，并已成为一个公共卫生问题。这项研究的结果不仅将增强我们对病毒发病机制的理解；它们还将导致制定预防和治疗新生儿脑炎的新战略。

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.