Stat 1 modification for antiviral defense

病毒是急性和慢性病最常见的原因之一，也是新发现的病毒 继续引起抵抗现有疫苗的新出现的疾病。尽管这个问题的范围很广，但 大多数病毒感染，特别是新型感染的诊断和治疗效果的准确性是 在有效性上非常有限。为了解决这个问题，我们制定了另一种战略，旨在 在定义和改进抗病毒宿主反应方面。我们特别关注呼吸道感染。 因为这是自然感染的常见途径，也是传递生物恐怖威胁的可能途径。在那 在这方面，我们开发了一种原代培养和感染人呼吸道上皮细胞的系统，该系统 对体内发现的行为表现出高度的保真度。我们对这一上皮细胞模型的分析与一个 相应的小鼠模型表明，对呼吸道病毒感染的抗病毒防御依赖于 关键在于干扰素(干扰素)对呼吸道上皮细胞失速信号分子的激活。基于 这些发现，我们提出，改善呼吸道上皮细胞的失速功能将增强抗病毒作用 防守。因此，我们设计了一个带有战略性双半胱氨酸突变的改良摊位(设计 SLAL1-CC)，对内源性干扰素水平高反应。因此，失速CC的表达应该 增强干扰素信号传递功能，更好地控制病毒复制。的确，我们的 初步研究表明，Stall-CC的表达显著降低了病毒复制水平 在体外(使用转导细胞)和体内(使用转基因或基因转移技术)。例如, 携带Stall-CC转基因或经Stall-CC基因转移载体处理的小鼠完全保护 预防因迄今研究的三种病毒中的每一种而造成的致命性感染。此外，我们还拥有 未观察到Stall-CC表达的毒性，与直接给药或 干扰素本身的过度表达。在这项提案中，我们的目标是将我们的方法扩展到对突发事件的研究 具有流行能力的病原体在人群中传播。通过这样做，我们的目标是 建立这些新病毒的感染能力和诊断特征，这是一种新的治疗策略 对于这些病原体，以及对这些病原体的先天免疫力有更好的了解。

Viruses are among the most frequent causes of acute and chronic illness, and newly discovered viruses continue to cause emergent diseases that resist established vaccines. Despite the scope of this problem, the accuracy of diagnosis and efficacy of treatment for most viral infections, especially new types of infections, is very limited in effectiveness. To address this issue, we have developed an alternative strategy that is aimed at defining and then improving the antiviral host response. We focus particularly on respiratory infection since this is a common route of natural infection and a likely route for delivery of bioterrorist threats. In that regard, we have developed a system for primary-culture and infection of human airway epithelial cells that exhibits high fidelity to behavior found in vivo. Our analysis of this epithelial cell model in concert with a corresponding mouse model indicates that antiviral defense against respiratory viral infection depends critically on interferon (IFN) activation of the Stall signaling molecule in airway epithelial cells. Based on these findings, we proposed that improving Stall function in airway epithelial cells would enhance antiviral defense. Accordingly, we engineered a modified Stall with strategic double-cysteine mutalions (designaled Slal1-CC) that is hyperresponsive to endogenous interferon levels. Expression of Stall-CC should thereby enhance interferon-signaling function and provide for better control of viral replication. Indeed, our Preliminary Studies demonstrate that Stall-CC expression markedly decreases Ihe level of viral replication both in vitro (using transduced cells) and in vivo (using transgenic or gene transfer technology). For example, mice carrying the Stall-CC transgene or treated with a Stall-CC gene-transfer vector are fully protected against otherwise lethal infections due to each of the three viruses studied thus far. Furthermore, we have observed no toxicities of Stall-CC expression, in contrast to the situation for direct administralion or overexpression of interferon itself. In this proposal, we aim to extend our approach to the study of emergent pathogens with the capability for epidemic spread through the human population. In doing so, we aim to establish infection capabilities and diagnostic signatures for these new viruses, a new therapeutic strategy for these pathogens, and a better understanding of innate immunity to these agents.