Microbiome-derived small molecules and host resistance against Vibrio cholerae

微生物组衍生的小分子和宿主对霍乱弧菌的抵抗力

• 批准号: 10867140
• 负责人: Luis Caetano Martha Antunes
• 金额: $ 21.21万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10867140
• 关键词: Anti-Infective Agents; Bacteria; Biological Assay; Biology; Categories; Chemicals; Cholera; Collection; Communicable Diseases; Communication; Complex; Development; Environment; Feces; Food; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; Health; Host resistance; Human; Human body; Immune system; Infection; Mass Spectrum Analysis; Microbe; Modeling; Nature; Nuclear Magnetic Resonance; Pathogenesis; Pathogenicity; Phenotype; Play; Property; Repression; Role; Salmonella enterica; Signal Transduction; Signaling Molecule; Source; Therapeutic; Vibrio cholerae; Virulence; Work; cell motility; fecal metabolome; gene repression; gut microbiota; human pathogen; insight; microbial community; microbiome; microbiota; microbiota metabolites; pathogen; response; small molecule; transcriptome; virulence gene

The human body is colonized by a complex microbial community with critical roles for health. This microbiota educates the immune system, helps digest our food, and protects us against pathogens. The diversity of microbes and encoded functions is significant. Our group showed that the gut microbiota is also a source of great chemical diversity, and that most of the compounds produced are unknown. Bacteria produce and respond to small molecules to communicate and adapt to their environment. Chemical signaling controls functions that are critical for host adaptation in most pathogens. Therefore, small-molecule signaling is an attractive target for the development of anti-infectives. Given the chemical complexity of the gut, microbiotapathogen crosstalk must be common. In fact, we previously showed that an organic extract of human feces elicits a significant transcriptional response in Salmonella enterica, with ~100 regulated genes. Interestingly, virulence genes were abundant among those repressed by the extract, suggesting that microbiota-derived metabolites can dampen virulence. We then determined that a single commensal, Enterocloster citroniae, can repress S. enterica virulence gene expression. More recently, we studied the transcriptional impact of the human fecal metabolome on other pathogens. In Vibrio cholerae, the causative agent of cholera, the effect was even more pronounced, with ~900 genes being regulated. Motility was the main category of repressed genes, and the effect was confirmed by phenotypic assays. As with S. enterica, the effect could be recapitulated with E. citroniae. Given the importance of V. cholerae as a human pathogen and the critical role played by motility in its pathogenesis, it is our goal to determine the impact of microbiota-derived metabolites on V. cholerae pathogenicity. We will generate a collection of gut commensals with anti-motility properties to characterize the genetic and chemical nature of the bioactivity. Genomes and transcriptomes of active and inactive strains will be compared, giving insights into the synthetic apparatus involved. Bioactivity-guided purification will be performed, and compound characterization using mass spectrometry and nuclear magnetic resonance will ensue. Lastly, we will study the impact of active strains and compounds on host resistance to V. cholerae using infection models. Results from this work will shed light on the chemical biology of microbiota-pathogen interactions and may reveal strains and compounds with potential therapeutic applications.

人体内有一个复杂的微生物群落，对健康起着关键作用。这种微生物群 教育免疫系统，帮助消化我们的食物，并保护我们免受病原体的侵害。之多样 微生物和编码功能是重要的。我们的研究小组表明，肠道微生物群也是一个来源， 巨大的化学多样性，产生的大多数化合物是未知的。细菌产生和 对小分子做出反应来交流和适应环境。化学信号控制 这些功能对于大多数病原体的宿主适应至关重要。因此，小分子信号传导是一种 是抗感染药物开发的有吸引力的目标。鉴于肠道的化学复杂性，微生物病原体 串扰必须是常见的。事实上，我们之前的研究表明，人类粪便的有机提取物 在肠道沙门氏菌中，通过~100个受调控的基因，产生显著的转录应答。有趣的是， 毒力基因在被提取物抑制的那些基因中是丰富的，这表明微生物来源的 代谢物可以抑制毒性。然后我们确定了一个单独的寄生虫，香茅肠梭菌， 可以抑制S.肠毒力基因表达最近，我们研究了 人类粪便代谢组对其他病原体的影响霍乱弧菌是霍乱的病原体， 影响甚至更明显，约有900个基因受到调控。运动是主要的类别， 抑制基因，并通过表型测定证实了该效果。与S。肠道，效果可能 用E.香茅。考虑到霍乱弧菌作为人类病原体的重要性和 运动在其发病机制中所起的作用，我们的目标是确定微生物来源的 代谢产物对霍乱弧菌致病性的影响。我们将收集一批具有抗运动性的肠肽 特性，以表征生物活性的遗传和化学性质。基因组和转录组 将比较活性和非活性菌株的数量，从而深入了解所涉及的合成装置。 将进行生物活性指导的纯化，并使用质谱法进行化合物表征 核磁共振也会随之而来。最后，我们将研究活性菌株和化合物的影响 宿主对霍乱弧菌的抗性。这项工作的结果将有助于了解这种化学物质 微生物-病原体相互作用的生物学，并可能揭示具有潜在治疗作用的菌株和化合物。 应用.