Flagellin-Induced Antiviral Activity

描述（由申请人提供）：病毒感染导致和/或促进了许多人类最棘手的健康问题。大多数病毒感染既不能预防也不能治愈，因此非常需要新的策略来对抗这些感染因子。本提案旨在通过调查我们最近发现的一种新的有效的先天免疫抗病毒机制来帮助填补这一鸿沟。具体来说，使用小鼠轮状病毒（RV）感染作为年轻小鼠急性腹泻诱导感染和免疫缺陷小鼠慢性感染的模型，我们最近取得了意想不到的观察结果，即全身给药细菌鞭毛蛋白可以预防或消除正在进行的轮状病毒感染。鞭毛蛋白的抗病毒作用不依赖于适应性免疫和干扰素（型和型），而需要造血细胞表达已知的鞭毛蛋白受体，toll样受体5 （TLR5）和Nod样受体C4 （NLRC4）。鞭毛蛋白对轮状病毒感染的阻断可能利用了通常介导细菌-病毒竞争/串扰的途径，或者被证明是一种纯粹的工程方法，不模仿体内自然发生的过程。无论如何，外源性给药鞭毛蛋白可以快速治愈慢性病毒感染，否则免疫受损的宿主无法解决这一问题，这表明，如果了解并利用这种机制，可能会为对抗一些继续困扰人类的众多病毒提供新的武器。因此，虽然开发治疗轮状病毒感染的新方法是本项目的一个潜在结果，但本提案的主要总体目标是确定鞭毛蛋白抗病毒作用的机制，以便可以利用它来开发治疗各种病毒感染的新策略。我们将采用一系列相互关联的遗传，免疫学和生化方法来定义细胞类型，可治愈和预防RV感染的可溶性介质，并破译其作用模式。

DESCRIPTION (provided by applicant): 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 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' 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.