EXPLORING THE C. ELEGANS TRANSCRIPTIONAL RESPONSE TO VIRAL INFECTION

描述（由申请人提供）：传染病在全球范围内造成巨大的发病率和死亡率负担。为了减轻由感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整个防御体系至关重要。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细胞应答的适应性途径和先天免疫机制，如干扰素介导的信号传导。然而，这不可能是所有抗病毒反应的全貌。事实上，它只是在过去的十年左右，基本的先天免疫途径，如RNA干扰（RNAi）和Toll样受体（TLR）的信号转导被发现，反映了有多少关于免疫系统的发现，并提出了额外的先天途径可能存在的明显可能性，今天仍然未被发现。模式生物在定义人类生物学的核心生物过程方面被证明是非常宝贵的。例如，TLRs的抗菌功能首先在果蝇的研究中被确定，而RNA干扰（RNAi）的开创性研究是在C.优雅然而，C. elegans模型在宿主-病毒免疫的研究中一直被忽视。应用C. elegans定义抗病毒宿主反应直接源于完全不存在能够感染C.优雅随着我们最近发现的第一个病毒能够感染小杆线虫和建立一个真正的实验病毒感染系统，它现在是第一次有可能探索生理相关的主机自然病毒感染的反应，在这个遗传上易于处理的模式生物。本研究的目的是：（1）在两种宿主中产生第一个定义宿主对病毒感染的转录反应的数据。briggsae和C. elegans，从而鉴定应答线虫病毒感染的共有基因组，和（2）通过消除作为Aim 1中定义的共有转录应答盒的一部分的基因来鉴定抗病毒基因。这些研究将为病毒感染诱导的转录网络提供第一个见解，并有可能定义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进化保守。 公共卫生相关性：该项目旨在了解病毒感染在线虫中诱导的基因和途径，以确定免疫的抗病毒机制。这些机制可能是保守的，并在人类对病毒的免疫中发挥重要作用。

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. PUBLIC HEALTH RELEVANCE: This project aims to understand the genes and pathways that are induced in nematodes by viral infection in order to define antiviral mechanisms of immunity. Such mechanisms may be conserved and play important roles in human immunity against viruses.