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: 10460636
• 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/10460636
• 关键词: Adult; Bacteria; Biochemistry; Cells; Computer Analysis; Cytolysis; Exclusion; Genes; Genome; Genomics; Health; Human; Hybrids; Immunity; Lead; 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.

肠道微生物群对人类健康的影响取决于物种的特性 其中。导致人与人之间微生物群组成差异的机制是 不太理解。我们专注于优势细菌之间的相互作用 西方成年人肠道中的分类群，拟杆菌目。这些细菌争夺空间 和营养物质通过称为 VI 型分泌系统 (T6SS) 的分子纳米武器。有毒的 T6SS 在相邻拟杆菌细胞之间传递的蛋白质效应子导致细胞统计 或裂解，我们和其他人之前已经揭示这种竞争会导致菌株水平 通过杀死目标细菌来排除微生物群的差异。由于效应器可以 编码 T6SS 的细菌会不加区别地递送至亲缘细胞，产生免疫因子， 专门中和同源效应器。我们之前已经发现了普遍存​​在的现象 拟杆菌科大型基因组阵列中编码的“孤儿”免疫因子 缺乏同源效应子的基因组。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 从微生物组中排除。在本提案中，我们试图了解这一机制 孤儿免疫基因被捕获并聚合到最常见的 AID 系统类型中，即 重组酶相关 AID (rAID) 系统，利用细菌遗传学的强大组合， 生物化学、宏基因组学和知识生物学。我们进一步寻求了解法规 rAID 系统通过假设的“竞争感知”发挥的生物地理作用 涉及混合传感器激酶途径的机制。我们共同致力于了解 拟杆菌对 T6SS 的防御对肠道微生物组的影响。