Functional analysis of flavivirus genetic resistance.

许多黄病毒，包括西尼罗河病毒（WNV），引起显著的人类发病率和死亡率 由于生产力的损失和医疗保健的延长，导致高成本。最终 病毒感染的结果是多种宿主和病毒成分之间复杂相互作用的结果。 小鼠的自然遗传变异为研究小鼠的易感性提供了一个独特的模型系统。 分子水平。小鼠中的单个基因（Flv）改变黄病毒产生和疾病的水平 结果。该基因在上一个资助期被鉴定为2 '-5'寡腺苷酸合成酶 (Oas)1b. Oas基因作为先天免疫应答的一部分发挥作用，产生2-5A，其激活 潜伏核糖核酸内切酶2-5A和RNase L都是病毒非特异性的。然而， 抗性Flv等位基因（Oaslbr）的产物是黄病毒特异性的，我们已经证明这种蛋白质不是一种特异性的蛋白质。 功能性2 '-5'寡腺苷酸合成酶。Oaslbr赋予黄病毒抗性的机制 表型未知。基于新的初步数据，我们假设Oaslbr可以调节 对黄病毒感染的快速细胞信号反应的激活， 不太支持病毒RNA复制的细胞环境，并且Oaslbr可以与病毒RNA相互作用。 基因组RNA减少病毒RNA基因组复制。这些目标提出了研究， 小鼠Oaslbr蛋白通过其赋予其黄病毒特异性抑制作用的途径。奥斯尔布尔 可以直接或间接地实现这些不同的效果。根据目标1，我们将调查RV- 特异性早期信号传导和基因上调反应WNV通过识别组件和 激活的途径，通过分析调节上调基因的转录因子/激活剂， 通过调查OASLBR在这些反应中的参与程度。在目标2下，我们将确定和 表征Oaslbr的细胞蛋白和病毒RNA结合配偶体，并分析这些可能的作用。 这些研究预计将导致发现新的 Oas/OAS蛋白的功能途径以及新的先天免疫抗病毒途径。这 研究有助于了解个体对黄病毒感染反应的差异， 人类

Many of the flaviviruses, including West Nile virus (WNV), cause significant human morbidity and mortality throughout the world resulting in high costs due to lost productivity and for extended health care. The final outcome of a viral infection is the result of a complex interaction between multiple host and viral components. A natural genetic variation in mice provides a unique model system for studying susceptibility at the molecular level. A single gene in mice (Flv) alters both the level of flavivirus production and disease outcome. This gene was identified during the previous funding period as 2'-5' oligoadenylate synthetase (Oas) 1b. Oas genes function as part of the innate immune response, producing 2-5A which activates the latent endoribonuclease, RNase L. Both 2-5A nor RNase L are virus non-specific. However, the effect of the product of the resistant Flv allele (Oaslbr) is flavivirus-specific and we have shown that this protein is not a functional 2'-5' oligoadenylate synthetase. The mechanism by which Oaslbr confers the flavivirus resistance phenotype is not known. Based on novel preliminary data, we hypothesize that Oaslbr can modulate activation of a rapid cell signaling response to flavivirus infection, that the set of genes up-regulatedcreates a cell environment less supportive of viral RNA replication and that Oaslbr can interact with the viral genomic RNAto reduce viral RNA genome replication. The aims propose studies to dissect the molecular pathway(s) through which the murine Oaslbr protein confers its flavivirus-specific inhibitory effect. Oaslbr may accomplish these various effects either directly or indirectly. Under Aim 1, we will investigate the RV- specific early signaling and gene up-regulation responses to WNV by identifying the componentsand pathways activated, by analyzing the transcription factors/activators regulating the up-regulated genes and by investigating the involvement of Oaslbr in these responses. Under Aim 2, we will identify and characterize cell protein and viral RNA binding partners of Oaslbr and analyze the possible roles of these proteins in modulating the resistance phenotype.These studies are expected to result in the discovery of new functional pathways for Oas/OAS proteins as well as of novel innate immune antiviral pathways. This research is relevant to understanding individual variation in the response to flavivirus infections among humans.