Flagellin-Induced Antiviral Activity

鞭毛蛋白诱导的抗病毒活性

• 批准号: 8655677
• 负责人: Andrew T Gewirtz
• 金额: $ 22.2万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8655677
• 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

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.

病毒感染引起和/或促进人类许多最棘手的健康问题。 最具病毒性 感染既无法预防也无法治愈，因此非常需要新的策略来应对 这些传染源。 该提案旨在通过调查我们最近令人震惊的情况来帮助填补这一鸿沟 发现存在一种新的有效的先天免疫抗病毒机制。 具体来说，使用 鼠轮状病毒（RV）感染作为急性腹泻模型——诱导幼鼠感染和 在免疫缺陷小鼠的慢性感染中，我们最近做出了意想不到的观察，系统性 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 抗病毒作用独立于适应性免疫和干扰素（I 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 受体 C4 (NLRC4)。 鞭毛蛋白对轮状病毒感染的阻断可能是利用通常的途径 介导细菌-病毒竞争/串扰或被证明是一种纯粹的工程方法，不会 模仿自然发生的体内过程。 无论如何，外源施用鞭毛蛋白的结果 快速治愈免疫受损无法解决的慢性病毒感染 主持人表示，如果理解和利用这种机制，可能会提供新的 对抗继续困扰人类的众多病毒中的一些的武器。因此，虽然 开发治疗轮状病毒感染的新方法是该项目的潜在成果之一 该提案的主要总体目标是确定鞭毛蛋白抗病毒作用的机制 行动，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 治疗和预防 RV 感染并破译其作用模式的类型、可溶性介质。