Functional analysis of flavivirus genetic resistance.

产品说明：许多黄病毒，包括西尼罗河病毒（WNV），在全世界引起显著的人类发病率和死亡率，导致由于生产力损失和延长的医疗保健而导致的高成本。病毒感染的最终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在分子水平上研究易感性提供了独特的模型系统。小鼠中的单个基因（Flv）改变黄病毒产生水平和疾病结果。该基因在上一个资助期间被鉴定为2 '-5'寡腺苷酸合成酶（Oas）1b。Oas基因作为先天性免疫应答的一部分发挥作用，产生2-5A，其激活潜在的核糖核酸内切酶RNase L。2-5A和RNase L都是病毒非特异性的。然而，抗性Flv等位基因（Oaslbr）的产物的作用是黄病毒特异性的，并且我们已经表明该蛋白质不是功能性的2 '-5'寡腺苷酸合成酶。Oaslbr赋予黄病毒抗性表型的机制尚不清楚。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传导应答的激活，上调的基因组产生不太支持病毒RNA复制的细胞环境，并且Oaslbr可以与病毒基因组RNA相互作用以减少病毒RNA基因组复制。这些目的提出研究来剖析小鼠Oaslbr蛋白赋予其黄病毒特异性抑制作用的分子途径。Oaslbr可以直接或间接地实现这些不同的效果。在目标1下，我们将通过鉴定激活的组分和途径、通过分析调节上调基因的转录因子/激活剂以及通过研究Oaslbr在这些应答中的参与来研究RV特异性早期信号传导和对WNV的基因上调应答。在目标2下，我们将鉴定和表征Oaslbr的细胞蛋白和病毒RNA结合伴侣，并分析这些蛋白在调节抗性表型中的可能作用。这些研究有望发现Oas/OAS蛋白的新功能途径以及新的先天免疫抗病毒途径。这项研究有助于了解人类对黄病毒感染反应的个体差异。

DESCRIPTION: 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 and 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-regulated creates a cell environment less supportive of viral RNA replication and that Oaslbr can interact with the viral genomic RNA to 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 components and 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.