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: 10274748
• 负责人: Benjamin Ross
• 金额: $ 32.73万
• 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/10274748
• 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; Phosphotransferases; Proteins; Regulation; Research; Role; System; Taxon; 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.

肠道菌群对人类健康的影响取决于该物种的身份 其中。导致人与人之间微生物群差异的机制是 不太了解。我们专注于主要成员之间的无菌互动 西方成年人肠道中的分类群，即杆菌。这些细菌竞争太空 和通过分子纳米媒体（称为VI型分泌系统（T6SS））的营养物质。有毒的 T6SS在相邻杆菌细胞之间传递的蛋白质效应导致细胞统计 或裂解，我们和其他人以前已经揭示了这项竞争会导致应变水平 通过杀死排除靶细菌，微生物群的差异。因为效果可以 被偶然地递送至亲属细胞，T6SS编码细菌会产生免疫学因素 特定中和同源效应。我们以前已经确定了普遍的存在 在大型基因组阵列中编码的“孤儿”免疫学因子 缺乏相关作用的基因组。这些获得的细菌间防御（AID）系统 通过中和认知作用和促进应变 - 使T6SS无效 排除微生物组。在此提案中，我们试图了解 将孤儿免疫基因捕获到最常见类型的援助系统中，即 重组酶相关的辅助（RAID）系统，使用细菌的强大组合， 生物化学，宏基因组学和gnotobiology。我们进一步寻求了解法规 突袭系统通过假设的“竞争感应”的生物地理作用 涉及混合传感器激酶途径的机制。我们在一起，旨在了解 对T6SS的防御对肠道微生物组的影响。