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: 10642737
• 负责人: Jessica L Hill
• 金额: $ 7.2万
• 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/10642737
• 关键词: Adaptive Immune System; Address; Adult; 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; 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; 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; model organism; 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.

项目摘要 炎症性和传染病是全球死亡的主要原因之一。协调和 免疫防御的调节对于打击感染和防止异常炎症至关重要 回答。这在胃肠道中尤为重要，其中潜在的病原体必须是 与共生微生物区分开。我们的肠道微生物社区（营养不良）的有害变化是 与许多疾病有关。在宿主 - 微叶相互作用的最前沿是肠道细胞，它充当 与我们的腔环境的关键障碍和接口。肠细胞具有先天免疫的曲目 受体和防御机制，使它们可以直接反应并调节肠道细菌。因此，他们 人们认为在建立和维持我们发展的有益共生关系中起着至关重要的作用 与我们的肠道菌群。值得注意的是，这些宿主 - 微生物相互作用的基本几个基本过程 保持不明的理解，包括肠细胞如何区分共生和病原体或 哪种肠细胞反应促进了肠道中的共同选择。该提议的长期目标 是确定肠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易于障碍和简单性来实现这一目标 模型有机体C.秀丽隐杆线虫提供了剖析复杂性所需的精细空间分辨率 基础宿主 - 微叶相互作用。秀丽隐杆线虫是肠道发育和先天免疫的模型 也在Natura拥有多样的肠道微生物组，使秀丽隐杆线虫成为研究微生物 - 诱导先天免疫反应。 AIM 1将确定细菌和特定于社区特定的免疫 通过评估肠细胞对 使用单细胞RNA测序（SCRNA-SEQ）使用共生和致病性肠道细菌。这将揭示独特 基于细菌暴露的整个肠道细胞之间的先天免疫特征。初步的 我们胚胎scrna-seq数据集的证据突出了几种在空间上不同的免疫基因，包括c- 型凝集素（CLEC），它们在哺乳动物中细菌识别中具有明确的作用。 AIM 2将确定 肠细胞如何通过测试先天免疫受体的作用来调节肠道中的共生定植， 特别是CLEC，在选择和维持共生细菌时。结合分子 生物学和显微镜技术，AIM 2将阐明识别和响应所需的CLEC人群 到共生肠道细菌。拟议的调查的结果将阐明如何调节先天免疫力 在整个肠道上的转录层面以及它如何贡献和维护 肠道中的宿主微生物关系。通过将秀丽隐杆线虫的障碍与创新的机制相结合 分析我们将推动秀丽隐杆线虫研究社区向前迈进，重要的是揭示了保守的途径 实现不仅限于秀丽隐杆线虫的可推广概念的创建。