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.

项目总结/摘要 RNA病毒对人类健康产生了巨大的影响。SARS-CoV-2只是许多RNA中最新的一种 病毒性人畜共患病，即使不考虑流行病，地方性RNA病毒的健康负担，特别是在 弱势群体的数量是巨大的。上皮细胞，丰富和暴露在粘膜表面，往往是最重要的。 首先被RNA病毒感染，因此通常是第一种检测和响应病毒的细胞类型。 感染然而，与循环免疫细胞不同，它们的体内行为不能从血液中测量 并且它们的离体行为可能与体内动力学不太相关。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。 我们的前期工作证明线虫RIG-I-like receptor（RLR）DRH-1在线虫中的表达与线虫的RIG-1相似。elegans 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），保护免受病毒和其他细胞内病原体的感染。我们 发现DRH-1对感染奥赛病毒有反应，奥赛病毒是一种单链、正义RNA病毒， 自然感染C.肠上皮细胞 本提案的目的是确定DRH-1在何处以及如何触发对奥赛病毒的耐药性 感染，并调查是否在C.线虫，缺乏已鉴定的干扰素同源物， 旁观者细胞的免疫反应。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，向邻近细胞发出信号 通过一种尚未描述的途径其基本原理是基于我们对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。我们的工作是创新的，因为我们追求的是知识产权，这与 I型干扰素（IFN-I）在人类中的反应，但令人兴奋的是，似乎通过新的因素，作为同系物的信号 在MAVS中，IRF 3、NFkB、TNF-α和IFN-1本身在C.线虫基因组 我们将通过三个具体目标来检验我们的假设：目标1）DRH-1/RLR在何处以及如何促进 C. elegans？目的2）在C. elegans？目的3）在C. elegans？预期成果 建立DRH-1/RLR用于触发保护性IPR免疫应答的信号级联， 肠上皮细胞C. elegans，并确定系统防御系统的组成部分。的 拟议中的研究意义重大，因为它也可能导致RNA病毒感染的新疗法 更好地理解上皮免疫防御和炎症性疾病。