Role of TRIM56 in Antiviral Innate Immunity

描述(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病毒，更好地了解这些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，在世界范围内造成严重的发病率和死亡率。抗流感药物的选择有限，以及抗药性流感病毒株和新的亚型不断出现，没有疫苗可供使用，这突出表明迫切需要设计新的广谱抗病毒疗法来抗击未来的流感暴发。在初步研究中，我们已经证明了在肺中大量表达的三聚体基序蛋白TRIM56具有抗甲型流感病毒的活性。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性免疫信号进行正向调节，尽管TRIM56的这两个活性似乎是解偶联的。我们推测，TRIM56是一种新的抗病毒宿主因子，它通过不同的机制限制流感病毒的传播并促进天然免疫信号的传递。我们提出了两个特定的目标，通过结合病毒-细胞培养系统、诱变研究、生化和细胞生物学方法来探索TRIM56在先天性抗病毒防御中的新作用。在目标1中，我们将鉴定介导流感病毒限制性的TRIM56的分子决定因素和抗病毒作用(S)。在目标2中，我们将研究TRIM56促进TLR3抗病毒信号转导的机制。拟议研究的完成将对TRIM56在先天抗病毒免疫中的作用产生重要的新知识，并为开发新的抗病毒策略来对抗流感和可能出现的其他病毒感染提供新的线索。

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.