Role of TRIM56 in Antiviral Innate Immunity

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病毒，更好地了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，在世界范围内引起显著的发病率和死亡率。抗流感药物的选择有限，沿着耐药流感病毒株和无疫苗可用的新亚型的不断出现，突出了设计新的广谱抗病毒疗法以对抗未来流感爆发的迫切需要。在初步研究中，我们已经证明TRIM56，一种在肺中大量表达的三重基序蛋白，具有抗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）途径正向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偶联的。我们假设TRIM56是一种新型的抗病毒宿主因子，通过不同的机制限制流感病毒的繁殖并促进先天免疫信号传导。我们提出了两个具体的目标，探索TRIM56在先天性抗病毒防御中的新作用，通过结合使用病毒细胞培养系统，诱变研究，生物化学和细胞生物学方法。在目的1中，我们将表征TRIM 56介导流感病毒限制的分子决定簇和抗病毒作用。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，并为开发针对流感和其他可能出现的病毒感染的新型抗病毒策略提供新的思路。

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.