Role of TRIM56 in Antiviral Innate Immunity

TRIM56 在抗病毒先天免疫中的作用

• 批准号: 8604677
• 负责人: KUI LI
• 金额: $ 18.75万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604677
• 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）：宿主细胞已经进化出复杂的内在机制来检测和限制入侵的病毒，更好地理解这一机制对于开发安全有效的抗病毒疗法至关重要。流感病毒是医学上重要的病毒病原体，在全世界引起显着的发病率和死亡率。抗流感药物的选择有限，加上耐药流感病毒株和尚无疫苗可用的新亚型的不断出现，凸显了设计新的广谱抗病毒疗法来应对未来流感爆发的迫切需要。在初步研究中，我们已经证明TRIM56是一种在肺部大量表达的三联基序蛋白，具有针对甲型流感病毒的抗病毒活性。我们还发现 TRIM56 通过 Toll 样受体 3 (TLR3) 途径积极调节干扰素诱导的先天免疫信号传导，尽管 TRIM56 的这两种活性似乎是不相关的。我们假设 TRIM56 是一种新型抗病毒宿主因子，可通过不同的机制限制流感病毒传播并促进先天免疫信号传导。我们提出了两个具体目标，通过结合使用病毒-细胞培养系统、诱变研究、生化和细胞生物学方法来探索 TRIM56 在先天抗病毒防御中的新作用。在目标 1 中，我们将描述 TRIM56 介导流感病毒限制的分子决定因素和抗病毒作用。在目标 2 中，我们将研究 TRIM56 促进 TLR3 抗病毒信号传导的机制。完成拟议的研究将产生关于 TRIM56 在先天抗病毒免疫中的作用的重要新知识，并为针对流感和可能的其他新出现的病毒感染的新型抗病毒策略的开发提供新的线索。