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Discovery of immunomodulatory gut microbes with MAGIC

利用 MAGIC 发现免疫调节肠道微生物

基本信息

批准号：
9808632
负责人：
Ivaylo Ivanov Ivanov
金额：
$ 19.81万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-03 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808632
关键词：
Animals Antigens Biology CD4 Positive T Lymphocytes Collection Communities Complement Data Engineering Future Generations Genetic Goals Habitats Health Horizontal Gene Transfer Human Immune Immune response Immune system Immunity Immunoglobulin A In Situ In Vitro Individual Intestines Laboratories Lymphocyte Metagenomics Microbe Modeling Mucous Membrane Mus Nature Organism Organism Strains Phenotype Proteins Reporter Resources Sampling Specificity System T cell response T-Lymphocyte Testing Therapeutic Therapeutic Uses Transgenic Mice Transgenic Organisms biobank commensal bacteria commensal microbes experimental study food antigen genetic manipulation genetic payload gut microbes gut microbiome gut microbiota human microbiota immune activation immunogenic immunoregulation in vivo member microbiota mucosal vaccine novel pathogen tool trait

项目摘要

PROJECT SUMMARY Commensal microbes have profound effects on human health. However, the nature of the commensal microbes that stimulate and regulate the immune system of the host is largely unknown. Therefore, the mechanisms by which such microbes engage host immunity are unknown. However, genetic tools to study immune effects of the microbiota are currently not available. Moreover, it is unclear how many of the microbiota species are amenable to genetic manipulation. Generation of TCR transgenic mice against individual commensal microbes is an important approach to study such immune responses. However, generation of individual TCR Tg mice against the hundreds of microbiota species is a monumental task. Here, we propose an alternative approach, in which we will use a single TCR Tg mice to track T cell responses to most of the microbiota and identify immunomodulatory commensal species. To this goal we developed an approach for Metagenomic Alteration of Gut microbiome by In situ Conjugation, or MAGIC. MAGIC leads to expression of exogenous proteins in a broad range of microbiota species simultaneously. We will use this system to 1) create a biobank of genetically-modified commensal microbes that express immunogenic proteins; 2) identify and isolate immunogenic commensals and 3) characterize the generated T cell responses.

项目概要共生微生物对人类健康有着深远的影响。然而，共生体的性质刺激和调节宿主免疫系统的微生物在很大程度上是未知的。因此，这些微生物参与宿主免疫的机制尚不清楚。然而，用于研究的遗传工具目前尚不清楚微生物群的免疫作用。此外，尚不清楚其中有多少微生物群物种适合基因操纵。抗TCR转基因小鼠的产生个体共生微生物是研究此类免疫反应的重要方法。然而，培育针对数百种微生物群的 TCR Tg 小鼠个体是一项艰巨的任务。在这里，我们提出了一种替代方法，其中我们将使用单个 TCR Tg 小鼠来追踪 T 细胞对大多数微生物群的反应并识别免疫调节共生物种。为了这个目标我们开发了一种通过原位接合（MAGIC）改变肠道微生物组宏基因组的方法。 MAGIC 导致外源蛋白同时在多种微生物群中表达。我们将使用这个系统来 1) 创建一个转基因共生微生物生物库，这些微生物表达免疫原性蛋白质； 2) 识别和分离免疫原性共生体，3) 表征生成的共生体 T 细胞反应。