IFN actions and immune cell activation by West Nile Virus

西尼罗河病毒（WNV）是广泛传播于世界各地的许多嗜神经黄病毒之一， 并继续导致显著的发病率和死亡率。仅在美国就有24,000例 自2006年以来，人类西尼罗河病毒感染和1 000人死亡。先天性和适应性免疫成分， 包括CDS、CD 4 T细胞和B细胞有助于WNV清除并防止神经元感染。的 适应性免疫成分也形成记忆，这是疫苗接种策略的标志。的 获得性免疫的产生与先天激活有关，主要通过宿主模式的病毒感应 识别受体（PRR），这反过来又导致ARC激活和炎症反应的产生。 调解员这些早期炎症介质中的一类，I型干扰素（IFN-I）诱导抗病毒免疫应答。 在被感染的细胞和邻近的细胞中。许多病毒，包括西尼罗河病毒，发展了有效的干扰素-I逃避， 战略布局我们实验室和其他实验室的最新研究表明，IFN-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;但对特异性免疫应答的作用知之甚少。 模式识别受体和IFN-信号在产生黄病毒特异性适应性反应。一个 理解这一点对于生产改进的疫苗至关重要。我们假设IFN-I信号在 在产生WNV特异性适应性免疫中的关键作用， 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传导的作用， 通过RNA解旋酶和TLR用于产生WNV特异性CDS T细胞应答。在目标2中，我们将研究 IFN-I信号传导在WNV特异性CDS T细胞应答产生中的作用。在目标3中，我们将评估 IFN-I信号在编程T细胞应答中的时机的重要性。利用获得的知识 根据这些研究和U19其他四个项目中提出的研究，在目标4中，我们将调节IFN-1 信号传导作为增强疫苗接种的手段。因此，该提案将有助于实现多项目 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.