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.

项目摘要共生微生物对人类健康具有深远的影响。但是，共生的本质刺激和调节宿主免疫系统的微生物在很大程度上未知。因此，这种微生物使宿主免疫的机制尚不清楚。但是，研究的遗传工具菌群的免疫作用目前尚不可用。而且，目前尚不清楚多少微生物群可以适合基因操纵。 TCR转基因小鼠的产生单个共生微生物是研究这种免疫反应的重要方法。然而，针对数百种菌群物种的单个TCR TG小鼠的产生是一项巨大的任务。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小鼠跟踪T细胞对大多数微生物群的反应并确定免疫调节性共生物种。为了这个目标我们开发了一种通过原位共轭或魔术对肠道微生物组元基因组改变的方法。魔术同时导致外源蛋白在广泛的微生物群中表达。我们将使用此系统到1）创建一个表达遗传改性的共生微生物的生物库免疫原性蛋白； 2）识别和隔离免疫原性和3） T细胞反应。