EXPLORING THE C. ELEGANS TRANSCRIPTIONAL RESPONSE TO VIRAL INFECTION

描述(申请人提供)：传染病在世界范围内造成巨大的发病率和死亡率负担。为了减轻由感染微生物引起的疾病负担，全面了解宿主对微生物感染的整个防御体系是至关重要的。我们目前对抗病毒宿主防御机制的了解包括广泛的分支和效应器机制，包括基于抗体和T细胞反应的适应性途径和先天免疫机制，如干扰素介导的信号转导。然而，这不太可能是所有抗病毒反应的全貌。只有在过去十年左右才发现基本的先天免疫途径，如RNA干扰(RNAi)和Toll样受体(TLRs)信号传递，这一事实反映了关于免疫系统还有很多有待发现的地方，并提出了一种明显的可能性，即可能存在更多至今仍未发现的先天途径。事实证明，模式生物在定义人类生物学核心的生物过程方面具有非常宝贵的价值。例如，TLRs的抗菌功能最早是在果蝇的研究中确定的，而RNA干扰(RNAi)的开创性研究是在线虫中进行的。然而，在宿主病毒免疫的研究中，线虫模型在很大程度上被忽视了。应用线虫来确定抗病毒宿主反应的努力很少，直接原因是完全没有能够感染线虫的病毒。随着我们最近发现了第一种能够感染线虫的病毒，并建立了一个真正的实验病毒感染系统，现在第一次有可能在这种遗传上容易处理的模式生物中探索与生理相关的宿主对自然病毒感染的反应。这项建议的目的是(1)在线虫和线虫中产生第一个定义宿主对病毒感染的转录反应的数据，从而确定对线虫病毒感染做出反应的一组共识基因，以及(2)通过耗尽目标1中定义的共识转录反应盒中的基因来识别抗病毒基因。这些研究将提供对病毒感染诱导的转录网络的首次洞察，并有可能确定在线虫中发挥抗病毒作用的基因，这些基因在人类或哺乳动物中也可能在进化上保守。

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.