Functional analysis of flavivirus genetic resistance.

描述：包括西尼罗河病毒(WNV)在内的许多黄病毒在世界各地导致严重的人类发病率和死亡率，导致生产力损失和延长医疗保健的高昂成本。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一个独特的模型系统。小鼠体内的单个基因(Flv)改变了黄病毒的产生水平和疾病结局。该基因在之前的资助期间被鉴定为2‘-5’寡腺苷合成酶(OAS)1b。Oas基因作为先天免疫反应的一部分，产生2-5A，激活潜在的核糖核酸酶--核糖核酸酶L。2-5A和核糖核酸酶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的，我们已经证明该蛋白不是一个功能性的2‘-5’寡腺苷合成酶。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反应的激活，一组上调的基因创造了一个不太支持病毒RNA复制的细胞环境，并且Oaslbr可以与病毒基因组RNA相互作用来减少病毒RNA的基因组复制。该研究旨在剖析小鼠Oaslbr蛋白赋予其黄病毒特异性抑制作用的分子途径(S)。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成分和途径，通过分析调节上调基因的转录因子/激活子，以及通过调查Oaslbr参与这些反应，来研究轮状病毒特异性的早期信号和基因上调对西尼罗河病毒的反应。在目标2中，我们将鉴定和鉴定Oaslbr的细胞蛋白和病毒RNA结合伙伴，并分析这些蛋白在调节耐药表型中的可能作用。这些研究有望发现OAS/OAS蛋白的新功能途径，以及新的天然免疫抗病毒途径。这项研究与了解人类对黄病毒感染反应的个体差异有关。

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.