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。

• 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
• 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' 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

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.

项目摘要 肠道微生物群对免疫系统的功能有巨大的影响。 动态平衡和炎症性侮辱。大多数研究都集中在个体如何 细菌或特定的细菌配置与免疫系统相互作用，但 微生物区系包含其他形式的微生物生命，包括原生生物。几个物种 小鼠中常见的和非致病的原生生物，来自滴虫属，诱导出一种类型 2小肠的免疫反应，不引起明显的病理改变。此外，其他 滴虫的种类后来被发现，它们促进Th1和Th17细胞在 冒号。然而，目前尚不清楚粘膜免疫的这些差异是否与物种有关- 特定的影响或其他因素。肠道系统发育关系的研究进展 由于Tritrichmonas的基因组仍未测序，人们对它们的了解很少。 此外，免疫格局和微生物区系组成在不同地区之间差异很大。 小肠和结肠，这使它们之间的比较更加复杂 滴虫种类及其免疫效果。为了克服这些障碍，我们孤立了 两种能在小鼠体内引起Th1或Th2免疫反应的滴虫 肠子。在目标1中，我们将为每个原生生物生成高质量的基因组，并测量它们的 关键的免疫调节代谢物的输出。在目标2中，我们将描述 这两个原生生物在适应性免疫系统上。我们将确定免疫机制 对每一种滴虫都有反应。最后，在目标3中，我们将确定如何 这两种滴虫在小鼠模型中影响克罗恩病。这些研究将 建立关键的基因组工具和对滴虫种类和机制的见解 对肠道免疫功能的影响。此外，该项目将评估可能的好处 这些共生原生菌对克罗恩氏病的治疗，导致了新的治疗方法 治疗IBD。