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: 10181790
• 负责人: Michael R Howitt
• 金额: $ 48.74万
• 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/10181790
• 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; Epithelial; 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; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Mucosal Immunity; Mus; Output; Pathology; Phylogenetic Analysis; Production; RNA; Research; 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; base; effector T cell; enteric pathogen; experimental study; genomic data; genomic tools; gut microbiome; gut microbiota; immune system function; immunoregulation; in vivo; inflammatory disease of the intestine; 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 肠道微生物组对免疫系统的功能产生巨大影响， 稳态和炎症损伤期间。大多数研究都集中在个人如何 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，包括原生生物。几种 小鼠中常见的非致病性原生生物，来自三毛滴虫属， 2.小肠内的免疫反应，而不引起明显的病理。此外，其他 后来发现三毛滴虫的种类促进Th 1和Th 17细胞在 结肠然而，尚不清楚粘膜免疫的这些差异是否与物种有关- 具体影响或其他因素。肠上皮细胞的系统发育关系 对三毛单胞菌的了解很少，因为它们的基因组尚未测序。 此外，免疫景观和微生物群组成在不同地区之间差异很大。 小肠和结肠，这进一步使这些之间的比较复杂化， 三毛滴虫及其免疫作用。为了克服这些障碍，我们隔离了 两种三毛滴虫，在小细胞中引起Th 1或Th 2免疫应答， 肠子在目标1中，我们将为每种原生生物生成高质量的基因组，并测量它们的 关键免疫调节代谢物的输出。在目标2中，我们将描述 这两种原生生物对适应性免疫系统的影响。我们将确定免疫机制 对每种三毛滴虫都有反应最后，在目标3中，我们将确定如何 这两种三毛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洞察三毛滴虫物种和机制， 影响肠道免疫力。此外，该项目将评估可能的效益 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IBD。