IFN actions and immune cell activation by West Nile Virus

西尼罗河病毒(West Nile Virus，WNV)是广泛传播于世界各地的多种嗜神经性黄病毒之一， 并继续造成严重的发病率和死亡率。仅在美国就有2.4万例 自2006年以来，人感染西尼罗河病毒，1000人死亡。包括先天免疫和获得性免疫成分， 包括CDS、CD4T细胞和B细胞有助于清除西尼罗河病毒，防止神经元感染。这个 适应性免疫成分也形成记忆，这是疫苗接种策略的标志。这个 获得性免疫的产生与先天激活有关，主要是通过宿主模式的病毒感知 识别受体(PRRs)，进而导致ARC激活和炎症的产生 调解人。其中一类早期炎症介质，L干扰素(干扰素-I)诱导抗病毒 感染细胞和邻近细胞中的状态。包括西尼罗河病毒在内的许多病毒产生了强大的干扰素-I逃避能力 战略。我们和其他实验室最近的研究表明，干扰素-I也可以对T细胞产生深远的影响 细胞反应和免疫记忆的产生；但对特定的作用知之甚少 模式识别受体和干扰素信号在黄病毒特异性适应性反应中的作用。一个 了解这一点对于生产改进的疫苗至关重要。我们假设干扰素-I信号在 在产生西尼罗河病毒特异性获得性免疫中的关键作用以及干扰病毒干扰素-I的策略 规避机制应该产生更好的疫苗。在目标1中，我们将定义树突状细胞信号转导的作用 通过RNA解旋酶和TLR产生西尼罗河病毒特异性CDS T细胞反应。在目标2中，我们将研究 干扰素-I信号在西尼罗河病毒特异性CDS T细胞应答中的作用在目标3中，我们将评估 干扰素-I信号时序在编程T细胞反应中的重要性。利用所获得的知识 根据这些和在U19的其他四个项目中提出的研究，在目标4中，我们将调节干扰素-I 发送信号作为加强疫苗接种的手段。因此，这项建议将有助于实现多项目 这是U19的目标。

West Nile Virus (WNV) is one of the many neurotropic flaviviruses that is widely spread throughout the world, and continues to cause significant morbidity and mortality. In the US alone there were 24,000 cases of human WNV infection and 1000 fatalities since 2006. Both innate and adaptive immune components, including CDS, CD4 T cells and B cells contribute to WNV clearance and prevent infection of neurons. The adaptive immune components also form memory, which is the hall-mark for vaccination strategies. The generation of adaptive immunity is linked to innate activation, primarily via viral sensing by host pattern recognition receptors (PRRs), which in turn lead to ARC activation and generation of inflammatory mediators. One class of these early inflammatory mediators, type-l interferons (IFN-I) induce an anti-viral state in infected and neighboring cells. Many viruses, including WNV, developed potent IFN-I evasive strategies. Recent studies from our and other labs show that IFN-I can also exert profound influence on T cells responses, and generation of immune memory; but very little is known about the roles of specific pattern recognition receptors and the IFN-signaling in generating flavivirus-specific adaptive response. An understanding of this is critical for generating improved vaccines. We hypothesize that IFN-I signaling plays a critical role in generating WNV-specific adaptive immunity and that strategies to interfere with viral IFN-I evasive mechanisms should yield better vaccines. In Aim 1 we will define the role of dendritic cell signaling via RNA helicases and TLRs for generating WNV-specific CDS T cell responses. In Aim 2 we will examine the role of IFN-I signaling in the generation of WNV-specific CDS T cell responses. In Aim 3 we will assess the importance of the timing of IFN-I signals in programming T cell responses. Using the knowledge gained from these and the studies proposed in the other four projects of this U19, in Aim 4 we will modulate IFN-I signaling as means to enhance vaccination. Thus, this proposal will contribute to attainment of multi-project objectives of this U19.