Role of TRIM56 in Antiviral Innate Immunity

TRIM56 在抗病毒先天免疫中的作用

• 批准号: 8510314
• 负责人: KUI LI
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510314
• 关键词: Antiviral Agents; Antiviral Response; Antiviral Therapy; Binding; Biochemical; Biological; Bovine Viral Diarrhea Viruses; Cell Culture System; Cells; Development; Drug resistance; Epidemic; Family; Flaviviridae; Future; Genes; Goals; Hepatitis C virus; Immune; Immunity; Infection; Influenza; Influenza A virus; Integration Host Factors; Interferons; Invaded; Knowledge; Lead; Light; Lung; Mediating; Molecular; Morbidity - disease rate; Mutagenesis; Natural Immunity; Pathway interactions; Protein Family; Proteins; Public Health; RNA Viruses; Research; Retroviridae; Rhabdoviridae; Role; Signal Pathway; Signal Transduction; TRIM Motif; Vaccines; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; anti-influenza drug; base; combat; coping; design; human TLR3 protein; influenza outbreak; influenza virus strain; influenzavirus; information gathering; member; mortality; novel; pandemic disease; pathogen; public health relevance; respiratory virus; response; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Host cells have evolved elaborate intrinsic mechanisms to detect and restrict invading viruses, a better understanding of which is crucial for the development of safe and effective antiviral therapies. Influenza viruses are medically important viral pathogens that cause significant morbidity and mortality worldwide. The limited options for anti-influenza drugs, along with the constant emergence of drug-resistant influenza virus strains and new subtypes to which no vaccines are available, highlight the urgent need of designing new and broad-spectrum antiviral therapies to combat future influenza outbreaks. In preliminary studies we have demonstrated that TRIM56, a tripartite motif protein abundantly expressed in the lung, possesses antiviral activity against influenza A virus. We have also found that TRIM56 positively regulates innate immune signaling to interferon induction via the Toll-like receptor 3 (TLR3) pathway, although these two activities of TRIM56 seem to be uncoupled. We hypothesize that TRIM56 is a novel antiviral host factor that acts to restrict influenza virus propagation and to promote innate immune signaling through distinct mechanisms. We propose two specific aims to explore the novel roles of TRIM56 in innate antiviral defense through the combined use of virus-cell culture system, mutagenesis studies, biochemical and cell biological approaches. In Aim 1, we will characterize the molecular determinants and antiviral action(s) of TRIM56 that mediate the restriction of influenza virus. In Aim 2, we will investigate the mechanism by which TRIM56 promotes TLR3 antiviral signaling. Completion of the proposed studies will yield important new knowledge about the role of TRIM56 in innate antiviral immunity and shed new light on the development of novel antiviral strategies against influenza and possibly other emerging viral infections.

描述（由申请人提供）：宿主细胞已经发展出了详尽的固有机制，以检测和限制入侵病毒，更好地理解它对于开发安全有效的抗病毒药疗法至关重要。流感病毒是医学上重要的病毒病原体，在全球范围内引起明显的发病率和死亡率。抗激素药物的有限选择，以及不可用的疫苗可用的抗药性流感病毒菌株和新的亚型的持续出现，突出了迫切需要设计新的和广泛的抗病毒药抗病毒药疗法，以消除未来的流感疫情。在初步研究中，我们已经证明，Trim56是一种在肺中表达的三方基序蛋白，具有针对流感病毒的抗病毒活性。我们还发现，TRIM56通过Toll样受体3（TLR3）途径对干扰素诱导的先天免疫信号传导积极调节，尽管TRIM56的这两种活动似乎是未耦合的。我们假设TRIM56是一种新型的抗病毒宿主因子，可用于限制流感病毒传播并通过不同的机制促进先天的免疫信号传导。我们提出了两个特定的目的，旨在通过综合使用病毒细胞培养系统，诱变研究，生化和细胞生物学方法来探讨TRIM56在先天抗病毒防御中的新作用。在AIM 1中，我们将表征TRIM56的分子决定因素和抗病毒作用，从而介导了流感病毒的限制。在AIM 2中，我们将研究TRIM56促进TLR3抗病毒信号传导的机制。拟议研究的完成将产生有关TRIM56在先天抗病毒免疫中的作用的重要新知识，并为针对流感及其他新兴病毒感染的新型抗病毒策略的发展提供了新的启示。