Caenorhabditis Elegans: a Model for Genetic Interaction between the Gut Microbiota and Intestinal Epithelial Cells

秀丽隐杆线虫：肠道微生物群和肠上皮细胞之间遗传相互作用的模型

• 批准号: 10537455
• 负责人: Jessica L Hill
• 金额: $ 6.97万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537455
• 关键词: Adaptive Immune System; Address; Adult; Animal Model; Atlases; Bacteria; Biological Models; Biological Process; C-Type Lectins; Caenorhabditis elegans; Cause of Death; Cell Differentiation process; Cells; Communicable Diseases; Communities; Data; Data Set; Defense Mechanisms; Development; Disease; Embryo; Environment; Epithelial Cells; Escherichia coli; Exhibits; Exposure to; Foundations; Gastrointestinal tract structure; Gene Family; Genes; Genetic Models; Genetic Transcription; Home; Human; Immune; Immune response; Immunologic Receptors; Infection; Inflammatory; Inflammatory Response; Innate Immune Response; Intestines; Investigation; Maintenance; Mammals; Mediating; Mediator of activation protein; Microbe; Microscopy; Modeling; Molecular Biology; Natural Immunity; Organ; Pathogenicity; Pathway interactions; Pattern; Pattern recognition receptor; Play; Polysaccharides; Process; Protocols documentation; Pseudomonas aeruginosa; RNA Interference; Research; Research Personnel; Resolution; Role; Sales; Shapes; Surveys; System; Techniques; Testing; Training; Work; antimicrobial; base; career; cohort; commensal bacteria; commensal microbes; developmental genetics; dysbiosis; gut bacteria; gut microbes; gut microbiome; gut microbiota; host-microbe interactions; immune function; immunoregulation; improved; innovation; insight; intestinal epithelium; microbial; microbiome; microorganism; novel; oral vaccine; pathogen; prevent; receptor; response; single-cell RNA sequencing; targeted treatment; transcriptome

Project Summary Inflammatory and infectious diseases are among the leading causes of death worldwide. Coordination and regulation of immune defenses are essential to combating infection and preventing aberrant inflammatory responses. This is especially important within the gastrointestinal tract where potential pathogens must be differentiated from commensal microbes. Deleterious alterations in our gut microbial community (dysbiosis) are associated with numerous diseases. At the forefront of host-microbe interactions are intestinal cells which act as a critical barrier and interface with our luminal environment. Intestinal cells possess a repertoire of innate immune receptors and defense mechanisms, allowing them to directly respond to and modulate gut bacteria. Thus, they are thought to play a critical role in establishing and maintaining the beneficial symbiotic relationships we develop with our gut microbiota. Remarkably, several fundamental processes underlying these host-microbe interactions remain poorly understood, including how intestinal cells differentiate between commensals and pathogens or which intestinal cell responses promote commensal selection in the gut. The long-term objective of this proposal is to determine how intestinal cells directly contribute to the selection and maintenance of commensal gut bacteria. The proposed research approaches this objective by leveraging the tractability and simplicity of the model organism C. elegans to provide the fine-scale spatial resolution needed to dissect the intricacies underlying host-microbe interactions. C. elegans is a model of intestinal development and innate immunity that also harbors a diverse gut microbiome in natura, making C. elegans an excellent system for studying microbial- induced innate immune responses. Aim 1 will determine how bacteria- and community-specific immune responses are organized in the intestine by evaluating the transcriptional response of intestinal cells to commensal and pathogenic gut bacteria using single-cell RNA-sequencing (scRNA-seq). This will reveal unique innate immune signatures among intestinal cells throughout the gut based on bacterial exposure. Preliminary evidence from our embryo scRNA-seq dataset highlight several spatially distinct immune genes including the C- type lectins (CLECs), which have a well-defined role in bacterial recognition in mammals. Aim 2 will determine how intestinal cells regulate commensal colonization in the gut by testing the role of innate immune receptors, specifically CLECs, in selecting for and maintaining commensal bacteria. Using a combination of molecular biology and microscopy techniques, aim 2 will elucidate the cohorts of CLECs required to recognize and respond to commensal gut bacteria. Results from this proposed investigation will clarify how innate immunity is regulated on a transcriptional level throughout the intestine and how it contributes to the selection and maintenance of host-microbe relationships in the gut. By combining the tractability of C. elegans with innovative mechanistic analysis we will move the C. elegans research community forward and, importantly, reveal conserved pathways enabling the creation of generalizable concepts not limited solely to C. elegans.

项目概要 炎症和传染病是全世界导致死亡的主要原因之一。协调和 免疫防御的调节对于对抗感染和预防异常炎症至关重要 回应。这在胃肠道内尤其重要，因为潜在的病原体必须被排除在胃肠道内。 与共生微生物不同。我们肠道微生物群落的有害改变（菌群失调）是 与多种疾病有关。肠道细胞处于宿主与微生物相互作用的最前沿，其作用是 与我们的管腔环境的关键屏障和界面。肠道细胞拥有一系列先天免疫 受体和防御机制，使它们能够直接响应和调节肠道细菌。因此，他们 被认为在建立和维持我们发展的有益共生关系方面发挥着关键作用 与我们的肠道微生物群。值得注意的是，这些宿主-微生物相互作用背后的几个基本过程 仍然知之甚少，包括肠道细胞如何区分共生体和病原体或 哪些肠道细胞反应促进肠道内的共生选择。本提案的长期目标 是为了确定肠道细胞如何直接促进共生肠道的选择和维持 细菌。拟议的研究通过利用该方法的易处理性和简单性来实现这一目标 模型生物线虫提供解剖复杂性所需的精细空间分辨率 潜在的宿主-微生物相互作用。线虫是肠道发育和先天免疫的模型 自然情况下，秀丽隐杆线虫也拥有多样化的肠道微生物组，这使得秀丽隐杆线虫成为研究微生物的绝佳系统。 诱导先天免疫反应。目标 1 将确定细菌和群落特异性免疫如何 通过评估肠道细胞的转录反应来组织反应 使用单细胞 RNA 测序 (scRNA-seq) 分析共生菌和致病性肠道细菌。这将揭示独特的 基于细菌暴露的整个肠道肠道细胞之间的先天免疫特征。初步的 来自我们胚胎 scRNA-seq 数据集的证据突出了几个空间上不同的免疫基因，包括 C- 型凝集素（CLEC），在哺乳动物的细菌识别中具有明确的作用。目标 2 将决定 肠道细胞如何通过测试先天免疫受体的作用来调节肠道内的共生定植， 特别是 CLEC，用于选择和维持共生细菌。使用分子组合 生物学和显微镜技术，目标 2 将阐明识别和响应所需的 CLEC 群体 共生肠道细菌。这项拟议调查的结果将阐明先天免疫是如何调节的 在整个肠道的转录水平上以及它如何有助于选择和维持 肠道中宿主与微生物的关系。通过将线虫的易驯性与创新机制相结合 通过分析，我们将推动线虫研究界向前发展，重要的是，揭示保守的途径 能够创建可推广的概念，而不仅仅限于线虫。