Flagellin-Induced Antiviral Activity

病毒感染导致和/或促进人类许多最棘手的健康问题。 大多数病毒 感染既不能预防也不能治愈，因此非常需要新的战略来对抗 这些传染源。 这项建议旨在通过调查我们最近令人震惊的 发现存在一种新的有效的先天免疫抗病毒机制。 具体而言，使用 小鼠轮状病毒（RV）感染作为幼鼠急性腹泻诱导感染的模型， 免疫缺陷小鼠的慢性感染，我们最近意外地观察到， 施用细菌鞭毛蛋白可以预防或消除正在进行的轮状病毒感染。 弗拉格林氏 抗病毒作用不依赖于获得性免疫和干扰素（I型和II型）， 已知鞭毛蛋白受体Toll样受体5（TLR 5）和Nod样受体 受体C4（NLRC 4）。 鞭毛蛋白对轮状病毒感染的阻断作用可能是利用了通常 介导细菌-病毒竞争/串扰或证明是一种纯粹的工程方法， 模拟自然发生的体内过程。 无论如何，外源性鞭毛蛋白导致 在慢性病毒感染的快速治愈中， 主持人认为，如果理解和利用这种机制， 这些武器对付继续困扰人类的众多病毒中的一些。因此，虽然 开发治疗轮状病毒感染的新方法是该项目的一个潜在成果， 该提案的主要总体目标是确定鞭毛蛋白抗病毒的潜在机制 因此，它可以被用来开发新的策略来治疗各种病毒感染。 我们 将采用一系列相互关联的遗传学、免疫学和生物化学方法来定义细胞 类型，治疗和预防RV感染的可溶性介质，并解释其作用模式。

Viral infections cause and/or promote many of humanity's most intractable health problems. Most viral infections can neither be prevented nor cured thus leaving a great need for novel strategies to combat these infectious agents. This proposal seeks to help fill this chasm by investigating our startling recent discovery of the existence of a novel potent innate immune antiviral mechanism. Specifically, using murine rotavirus (RV) infection as a model of an acute diarrhea---inducing infection in young mice and a chronic infection in immune---deficient mice, we recently made the unexpected observation that systemic administration of bacterial flagellin could prevent or eliminate ongoing rotavirus infection. Flagellin's antiviral action was independent of adaptive immunity and interferon (type I and II) while requiring hemopoietic cell expression of both known flagellin receptors, toll---like receptor 5 (TLR5) and Nod---like receptor C4 (NLRC4). Flagellin's blockade of rotavirus infection may be utilizing pathways that normally mediate bacterial---viral competition/crosstalk or prove to be a purely engineered approach that does not mimic a naturally occurring in vivo process. Regardless, that exogenously administered flagellin results in rapid cure of chronic viral infections that would not otherwise be resolved by immune compromised hosts suggests the possibility that this mechanism, if understood and harnessed, might provide new weapons against some of the numerous viruses that continue to plague humanity. Thus, while development of new modalities to treat rotavirus infection is one potential outcome of this project, the primary overall goal of this proposal is to define the mechanism underlying flagellin's antiviral action so it can be harnessed to develop novel strategies to treat a variety of viral infections. We will employ a series of inter---related genetic, immunological and biochemical approaches to define the cell type(s), soluble mediator(s) that cure and prevent RV infection and decipher their mode of action.