Impact of symbiotic protists on intestinal T cell homeostasis and inflammation.

共生原生生物对肠道 T 细胞稳态和炎症的影响。

基本信息

批准号：
10570264
负责人：
Michael R Howitt
金额：
$ 49.22万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570264
关键词：
Adaptive Immune System Antibiotics Antigens Bacteria Biochemical CD4 Positive T Lymphocytes Cells Cellular Assay Colon Crohn&apos s disease Data Development Dietary Fiber Disease Disease Outcome Epithelium Equilibrium Fermentation Genes Genetic Genome Genomics Gnotobiotic Health Homeostasis Immune Immune response Immune signaling Immune system Immunity Immunology In Vitro Individual Inflammasome Inflammation Inflammatory Inflammatory Bowel Diseases Interferon Type II Intestines Kinetics Life Maps Measurement Measures Metabolic Metabolic Pathway Metabolism Mucosal Immunity Mus Output Pathology Phylogenetic Analysis Production Qualifying RNA Research Sensory Small Intestines Succinates T cell receptor repertoire sequencing T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Transgenic Organisms Tritrichomonas Work effector T cell enteric pathogen experimental study genome annotation genomic data genomic tools gut inflammation gut microbiome gut microbiota immune system function immunoregulation in vivo insight metabolomics microbial microbial genome microbiota mouse model nanopore novel therapeutic intervention pathobiont phenotypic data transcriptome transcriptomics

项目摘要

Project Summary The gut microbiome exerts a tremendous influence on the function of the immune system at homeostasis and during inflammatory insults. Most research has focused on how individual bacteria or particular bacterial configurations interact with the immune system, but the microbiota contains other forms of microbial life, including protists. Several species of common and non-pathogenic protists in mice, from the genus Tritrichomonas, induce a type 2 immune response in the small intestine without causing overt pathology. In addition, other species of Tritrichomonads were later discovered that promote Th1 and Th17 cells in the colon. However, it is unclear if these differences in mucosal immunity are related to species- specific effects or other factors. The phylogenetic relationship between intestinal Tritrichmonas species is poorly understood as their genomes remain unsequenced. Furthermore, the immune landscape and microbiota composition varies greatly between the small intestine and colon, which further complicates comparisons between these Tritrichomonas species and their immune effects. To overcome these obstacles, we isolated two species of Tritrichomonads that elicit either a Th1 or Th2 immune response in the small intestine. In Aim 1, we will generate high-quality genomes for each protist and measure their output of key immunomodulatory metabolites. In Aim 2, we will characterize the effects of these two protists on the adaptive immune system. We will determine immune mechanisms that respond to each species of Tritrichomonas. Finally, in Aim 3, we will determine how these two Tritrichomonads impact Crohn’s Disease in a mouse model. These studies will establish key genomic tools and insights into Tritrichomonas species and mechanisms that influence on intestinal immunity. Furthermore, this project will evaluate the possible benefits of these symbiotic protists on Crohns’s disease, leading to novel therapeutic approaches to treat IBD.

项目概要肠道微生物组对免疫系统的功能产生巨大影响大多数研究都集中在个体如何维持稳态和炎症损伤期间。细菌或特定的细菌结构与免疫系统相互作用，但微生物群包含其他形式的微生物生命，包括几种原生生物。小鼠中常见的非致病性原生生物，来自三滴虫属，诱导一种类型 2.小肠内的免疫反应不引起明显的病理改变。后来发现三滴虫种类可以促进 Th1 和 Th17 细胞的生长然而，尚不清楚粘膜免疫的这些差异是否与物种有关。肠道的特殊影响或其他因素的系统发育关系。由于三毛虫的基因组仍未测序，人们对它们知之甚少。此外，免疫环境和微生物群组成在不同物种之间差异很大。小肠和结肠，这进一步使这些之间的比较变得复杂为了克服这些障碍，我们分离了三滴虫属物种及其免疫作用。两种三滴虫在小细胞中引发 Th1 或 Th2 免疫反应在目标 1 中，我们将为每个原生生物生成高质量的基因组并测量它们。在目标 2 中，我们将描述关键免疫调节代谢物的影响。我们将确定这两种原生生物对适应性免疫系统的免疫机制。最后，在目标 3 中，我们将确定如何响应每种三滴虫。这两种三滴虫对小鼠模型中的克罗恩病有影响。建立关键基因组工具并深入了解三滴虫物种和机制此外，该项目将评估可能的益处。这些共生原生生物对克罗恩病的影响，导致了新的治疗方法治疗炎症性肠病。