EXPLORING THE C. ELEGANS TRANSCRIPTIONAL RESPONSE TO VIRAL INFECTION

描述（由申请人提供）：传染病在世界范围内造成了巨大的发病率和死亡率负担。为了减轻传染性微生物引起的疾病负担，全面了解宿主对微生物感染的全部防御机制至关重要。我们目前对抗病毒宿主防御机制的理解包括广泛的分支和效应机制，包括基于抗体和t细胞反应的适应性途径和先天性免疫机制，如干扰素介导的信号传导。然而，这不太可能是所有抗病毒反应的全貌。事实上，在过去的十年左右，基本的先天免疫途径，如RNA干扰（RNAi）和toll样受体（TLRs）的信号传导，才被发现，这反映了免疫系统还有多少有待发现的地方，并提出了一种明显的可能性，即可能存在其他尚未被发现的先天途径。模式生物在定义人类生物学的核心生物过程方面已被证明是无价的。例如，tlr的抗菌功能是在果蝇的研究中首次发现的，RNA干扰（RNAi）的开创性研究是在秀丽隐杆线虫中进行的。然而，秀丽隐杆线虫模型在宿主-病毒免疫的研究中很大程度上被忽视了。应用秀丽隐杆线虫来定义抗病毒宿主反应的努力的缺乏直接源于完全缺乏能够感染秀丽隐杆线虫的病毒。随着我们最近首次发现能够感染隐杆线虫的病毒，并建立了一个真正的实验病毒感染系统，现在有可能首次在这种遗传易感的模式生物中探索与自然病毒感染有关的生理宿主反应。该提案旨在(1)生成第一个定义线虫和秀丽隐杆线虫对病毒感染的宿主转录反应的数据，从而确定一组对线虫病毒感染作出反应的基因；(2)通过耗尽在Aim 1中定义的共识转录反应盒中的一部分基因来鉴定抗病毒基因。这些研究将首次深入了解病毒感染诱导的转录网络，并有可能确定在线虫中发挥抗病毒作用的基因，这些基因也可能在人类或哺乳动物中具有进化保守性。

DESCRIPTION (provided by applicant): Infectious diseases cause a tremendous burden of morbidity and mortality worldwide. In order to mitigate the disease burden arising from infectious microbes, it is critical to have a comprehensive understanding of the entire repertoire of host defenses against microbial infection. Our current understanding of antiviral host defense mechanisms encompasses a wide range of branches and effector mechanisms, including adaptive pathways based on antibody and T-cell responses and innate immune mechanisms, such as interferon mediated signaling. However, this is unlikely to be the complete picture of all antiviral responses. The fact that it has only been in the past decade or so that fundamental innate immune pathways, such as RNA interference (RNAi) and signaling by Toll-like receptors (TLRs), were discovered reflects how much remains to be discovered about the immune system and raises the distinct possibility that additional innate pathways may exist that remain undiscovered today. Model organisms have proven invaluable in defining biological processes central to human biology. For example, antimicrobial functions of TLRs were first identified in studies of Drosophila, and the seminal studies of RNA interference (RNAi) were performed in C. elegans. However, the C. elegans model has been largely ignored in the studies of host-viral immunity. The paucity of efforts to apply C. elegans to define antiviral host responses stems directly from the complete absence of viruses capable of infecting C. elegans. With our recent discovery of the first viruses capable of infecting Caenorhabditis nematodes and the establishment of a bona fide experimental viral infection system, it is now possible for the first time to explore physiologically relevant host responses to natural viral infection in this genetically tractable model organism. This proposal aims (1) to generate the first data defining the host transcriptional response to viral infection in both C. briggsae and C. elegans and thereby identify a consensus set of genes that respond to viral infection of nematodes and (2) to identify antiviral genes by depleting genes that are part of the consensus transcriptional response cassette defined in Aim 1. These studies will provide the first insights into the transcriptional networks induced by viral infection, and have the potential to define genes that play antiviral roles in nematodes that may also be evolutionarily conserved in humans or mammals.