Flagellin-Induced Antiviral Activity

鞭毛蛋白诱导的抗病毒活性

基本信息

批准号：
8785652
负责人：
Andrew T Gewirtz
金额：
$ 18.5万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-12 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8785652
关键词：
Acute Adverse effects Affect Antiviral Agents B-Lymphocytes Biochemical Biological Models Bone Marrow Cell Line Cells Chronic Coculture Techniques Dendritic Cells Development Diarrhea Engineering Epithelial Cells Flagellin Genetic Goals Health Humanities Immune Infection Infectious Agent Interferon Type I Interferon Type II Interferons Intestines Left Leukocytes Mediating Mediator of activation protein Modality Modeling Molecular Mus Natural Immunity Outcome Pathway interactions Plague Polyomavirus Prevention Process Production Relative (related person)Resistance Role Rotavirus Rotavirus Infections Series Small Intestines Source System T-Lymphocyte Therapeutic Toll-Like Receptor 5 Viral Virus Virus Diseases Work adaptive immunity cell type combat cytokine immune activation in vivo influenzavirus novel novel strategies prevent protective effect receptor response weapons

项目摘要

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.

描述（由申请人提供）：病毒感染导致和/或促进许多人类最棘手的健康问题。大多数病毒感染既无法预防也无法治愈，因此非常需要新的策略来对抗这些传染原。该提案旨在通过调查我们最近发现的一种新型有效的先天免疫抗病毒机制的惊人发现来帮助填补这一鸿沟。具体来说，我们最近使用鼠轮状病毒（RV）感染作为年轻小鼠的急性腹泻诱导感染和免疫缺陷小鼠的慢性感染模型，得出了意想不到的观察结果，即全身施用细菌鞭毛蛋白可以预防或消除持续的轮状病毒感染。鞭毛蛋白的抗病毒作用不依赖于适应性免疫和干扰素（II型和II型），同时需要造血细胞表达两种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，不能模仿自然发生的体内过程。无论如何，外源性施用鞭毛蛋白可以快速治愈慢性病毒感染，而免疫受损的宿主无法解决这种感染，这表明这种机制如果被理解和利用，可能会为继续困扰的众多病毒提供新武器。人类。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，但该提案的主要总体目标是确定鞭毛抗病毒作用的机制，以便可以利用它来开发治疗各种轮状病毒感染的新策略。病毒感染。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治疗和预防 RV 感染的细胞类型和可溶性介质，并破译它们的作用模式。