Flagellin-Induced Antiviral Activity

病毒感染导致和/或促进了人类许多最棘手的健康问题。最病毒式的 感染既不能预防也不能治愈，因此迫切需要新的战略来抗击 这些感染性病原体。这项提案试图通过调查我们令人震惊的最近 发现存在一种新的有效的先天免疫抗病毒机制。具体地说，使用 小鼠轮状病毒(RV)感染作为急性腹泻的模型-在幼鼠和 在免疫缺陷小鼠的慢性感染中，我们最近进行了意想不到的观察，即系统性感染 服用细菌鞭毛可以预防或消除持续的轮状病毒感染。鞭毛素 抗病毒作用独立于获得性免疫和干扰素(I型和II型)，而需要 鞭毛蛋白受体Toll样受体5(TLR5)和NOD样受体在造血细胞中的表达 C4受体(NLRC4)。鞭毛蛋白对轮状病毒感染的阻断可能利用了正常情况下 调节细菌-病毒竞争/串扰，或者证明是一种纯粹的工程方法，不 模仿活体内自然发生的过程。不管怎样，外源注射鞭毛蛋白的结果是 在快速治愈免疫受损无法解决的慢性病毒感染方面 Hosts建议，如果理解和利用这种机制，可能会提供新的 武器，以对抗继续困扰人类的众多病毒中的一些病毒。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， 这项提案的主要总体目标是确定鞭毛蛋白抗病毒的潜在机制 行动，以便可以利用它来开发治疗各种病毒感染的新战略。我们 将使用一系列相互关联的遗传、免疫学和生化方法来定义细胞 型(S)、可溶性介体(S)，治疗和预防轮状病毒感染并破译其作用模式。

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.