Mechanisms of adaptation to interbacterial antagonism by the human gut microbiota

人类肠道微生物群适应细菌间拮抗作用的机制

• 批准号: 10677885
• 负责人: Benjamin Ross
• 金额: $ 41万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677885
• 关键词: Adult; Bacteria; Biochemistry; Cells; Computer Analysis; Cytolysis; Exclusion; Genes; Genome; Genomics; Health; Human; Hybrids; Immunity; Metagenomics; Molecular; Nutrient; Orphan; Pathway interactions; Persons; Phosphotransferases; Proteins; Regulation; Research; Role; System; Taxon; antagonist; bacterial community; bacterial genetics; cell type; gut microbiome; gut microbiota; insight; lens; member; microbiome; microbiota; recombinase; sensor

The impact of the gut microbiota on human health depends on the identity of the species therein. The mechanisms that lead to differences in microbiota composition between people is not well understood. We focus on interbacterial interactions between members of the dominant taxon in the gut of Western adults, the order Bacteroidales. These bacteria compete for space and nutrients via a molecular nanoweapon known as the type VI secretion system (T6SS). Toxic protein effectors delivered between adjacent Bacteroidales cells by the T6SS result in cell statis or lysis, and we and others have previously revealed that this competition results in strain-level differences in the microbiota through exclusion of target bacteria via killing. Since effectors can be delivered indiscriminately to kin cells, T6SS-encoding bacteria produce immunity factors that specifically neutralize cognate effectors. We have previously identified the pervasive presence of “orphan” immunity factors encoded within large genomic arrays within Bacteroidales genomes that lack cognate effectors. These acquired interbacterial defense (AID) systems render the T6SS ineffective through neutralization of cognate effectors and facilitate strain- exclusion from microbiomes. In this proposal, we seek to understand the mechanism by which orphan immunity genes are captured aggregated into the most common type of AID system, the recombinase-associated AID (rAID) system, using a powerful combination of bacterial genetics, biochemistry, metagenomics, and gnotobiology. We further seek to understand the regulation and biogeographical role of rAID systems through a hypothesized “competition-sensing” mechanism that involves a hybrid sensor-kinase pathway. Together, we aim to understand the impact of Bacteroidales defense against the T6SS on the gut microbiome.

肠道微生物区系对人类健康的影响取决于物种的特性。 在那里。导致人与人之间微生物区系组成差异的机制是 不是很清楚。我们主要研究优势菌之间的细菌间相互作用。 西方成虫肠道中的分类单元，拟杆菌目。这些细菌争夺空间 和营养素通过一种被称为VI型分泌系统(T6SS)的分子纳米武器。毒物 T6SS在邻近类杆菌属细胞间传递的蛋白质效应物导致细胞统计 或裂解，我们和其他人之前已经透露，这场比赛的结果是菌株水平 通过杀灭目标细菌来排除微生物区系的差异。由于效应器可以 被不分青红皂白地传递给亲缘细胞，T6SS编码细菌产生免疫因子， 特别是中和同源效应器。我们之前发现了无处不在的存在 类杆菌属大基因组阵列中编码的“孤儿”免疫因子 缺乏同源效应器的基因组。这些获得性细菌间防御(AID)系统 通过中和同源效应器使T6SS无效，并促进应变- 被排除在微生物群之外。在这项建议中，我们试图了解通过什么机制 孤儿免疫基因被捕获并聚集到最常见的AID系统类型中 重组酶相关AID(RAID)系统，使用细菌遗传学的强大组合， 生物化学、超基因组学和灵知生物学。我们进一步寻求了解这项规定 和通过假想的“竞争感应”的突袭系统的生物地理作用 这一机制涉及到一种混合的传感器-激酶途径。我们共同致力于了解 类杆菌对T6SS的防御对肠道微生物群的影响。