Innate immunity against viral infection in intestinal epithelial cells of C. elegans

秀丽隐杆线虫肠上皮细胞对病毒感染的先天免疫

• 批准号: 10680767
• 负责人: Emily R Troemel
• 金额: $ 38.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680767
• 关键词: 2019-nCoV; Animals; Antiviral Response; Behavior; Binding; Blood; C. elegans genome; Caenorhabditis elegans; Cells; Data; Disease; Double-Stranded RNA; Epithelial Cells; Epithelium; Fluorescent in Situ Hybridization; France; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Health; Homologous Gene; Human; IRF3 gene; Immune; Immune response; Infection; Inflammatory; Innate Immune Response; Interferon Type I; Interferons; Intestines; Ions; Knowledge; Mammals; Measures; Methods; Microscopy; Microsporidia; Mission; Modeling; Molecular; Mucous Membrane; Muscle; NF-kappa B; Names; Natural Immunity; Nematoda; Neurons; Organism; Outcome; Pathway interactions; Pattern; Planets; Proteins; Proteomics; Public Health; RNA; RNA Interference; RNA Virus Infections; RNA Viruses; Regulation; Reporter; Research; Resistance; Role; Signal Pathway; Signal Transduction; Surface; System; TNF gene; Testing; Tissues; United States National Institutes of Health; Up-Regulation; Viral; Virus; Virus Diseases; Virus Replication; Visualization; Vulnerable Populations; Work; Zoonoses; antiviral immunity; burden of illness; candidate identification; cell type; cytosolic receptor; fighting; genetic analysis; helicase; in vivo; innovation; insight; intestinal epithelium; mutant; novel; overexpression; pandemic disease; pathogen; pathogenic fungus; receptor; response; tool; transcriptomics; tripolyphosphate; viral detection

Project Summary/Abstract RNA viruses have had an immense impact on human health. SARS-CoV-2 is only the most recent of many RNA viral zoonoses, and, even disregarding pandemics, the health burden of endemic RNA viruses, particularly in vulnerable populations, is substantial. Epithelial cells, abundant and exposed at mucosal surfaces, are often the first to be infected by RNA viruses, and are therefore often the first cell type to detect and respond to viral infection. However, unlike circulating immune cells, their in vivo behaviors cannot be measured from blood draws, and their behavior ex vivo may poorly correlate with in vivo dynamics. Our long-term goal is to understand how epithelial cells coordinate anti-viral responses in a whole-animal setting. Our previous work demonstrated that the RIG-I-like receptor (RLR) DRH-1 in the nematode C. elegans activates an anti-viral transcriptional response in intestinal epithelial cells that we named the Intracellular Pathogen Response (IPR), which protects against infections by viruses and other intracellular pathogens. We found that DRH-1 responds to infection with Orsay virus–a single-stranded, positive-sense RNA virus that naturally infects C. elegans intestinal epithelial cells. The objective of this proposal is to determine where and how DRH-1 triggers resistance to Orsay virus infection, and investigate whether in C. elegans, which lacks identified homologs of interferons, there is a role for bystander cells in mounting an immune response. The central hypothesis is that upon Orsay virus infection, DRH-1 in intestinal epithelial cells detects viral replication and induces the IPR, signaling to neighboring cells through an as-yet undescribed pathway. The rationale is based on our genetic analysis of DRH-1 and its role in anti-viral responses, and our visualization of IPR gene expression and DRH-1 localization dynamics in the context of infection. Our work is innovative because we are pursuing the IPR, which shares similarity with the type-I interferon (IFN-I) response in humans, but excitingly, appears to signal through novel factors, as homologs of MAVS, IRF3, NFkB, TNF-alpha and IFN-I itself are absent from the C. elegans genome. We will test our hypothesis with three specific aims: Aim 1) Where and how does DRH-1/RLR promote anti-viral defense in C. elegans? Aim 2) What signaling pathway is activated downstream of DRH-1/RLR in C. elegans? Aim 3) Which host cells mount an anti-viral immune response in C. elegans? The expected outcomes are to establish the signaling cascade used by DRH-1/RLR to trigger the protective IPR immune response in intestinal epithelial cells of C. elegans, and to identify the components of a systemic defense system. The proposed research is significant, because it could lead to new treatments for infections by RNA viruses, as well as a better understanding of epithelial immune defense and inflammatory diseases.

项目摘要/摘要 RNA病毒对人类健康有影响。 SARS-COV-2只是许多RNA中的最新 病毒人畜共患病，甚至无视大流行病，内部分子RNA病毒的健康燃烧，尤其是在 脆弱的人群是实质的。上皮细胞在粘膜表面丰富且暴露于粘膜表面，通常是 首先是由RNA病毒感染的，因此通常是第一种检测和反应病毒的细胞类型 感染。但是，与循环免疫细胞不同，它们的体内行为不能从血液中测量 绘画，其行为离体可能与体内动力学相关。我们的长期目标是了解 上皮细胞如何在整个动物环境中协调抗病毒反应。 我们以前的工作证明了线虫C.秀素的类似RIG-I样受体（RLR）DRH-1 激活肠上皮细胞中的抗病毒转录反应，我们将其命名为细胞内 病原体反应（IPR），可预防病毒和其他细胞内病原体的感染。我们 发现DRH-1对Orsay病毒的感染有反应 - 一种单链的阳性RNA病毒 自然感染秀丽隐杆线虫肠上皮细胞。 该提案的目的是确定DRH-1在何处以及如何触发对奥赛病毒的抵抗力 感染，并研究在缺乏干扰素同源物的秀丽隐杆线虫中是否有角色 用于安装免疫反应的旁观者细胞。中心假设是在奥赛病毒感染后， 肠上皮细胞中的DRH-1检测病毒复制并诱导IPR，发信号向相邻细胞发出 通过尚未描述的途径。理由是基于我们对DRH-1的遗传分析及其在 抗病毒反应，以及我们对IPR基因表达和DRH-1定位动态的可视化 感染的背景。我们的工作具有创新性，因为我们正在追求IPR，它与 I型干扰素（IFN-I）在人类中的反应，但令人兴奋的是，作为同源物的新因素发出了信号 秀丽隐杆线虫基因组中没有MAV，IRF3，NFKB，TNF-ALPHA和IFN-I本身。 我们将以三个特定的目的测试我们的假设：目标1）DRH-1/RLR在哪里以及如何促进 秀丽隐杆线虫中的抗病毒防御？ AIM 2）C中DRH-1/RLR的下游激活了哪些信号通路。 秀丽隐杆线？ AIM 3）哪些宿主细胞在秀丽隐杆线虫中安装抗病毒免疫反应？预期的结果 是建立DRH-1/RLR使用的信号传导级联反应，以触发受保护的IPR免疫反应 秀丽隐杆线虫的肠上皮细胞，并确定系统性防御系统的组成部分。这 拟议的研究很重要，因为它也可能导致RNA病毒感染的新治疗方法 为了更好地理解上皮免疫防御和炎症性疾病。