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.

人体被一个复杂的微生物群落殖民，在健康中至关重要。这个微生物群 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。多样性 微生物和编码功能很重要。我们的小组表明肠道菌群也是 伟大的化学多样性，并且生产的大多数化合物尚不清楚。细菌产生和 回应小分子以进行交流并适应其环境。化学信号控制 对于大多数病原体中宿主适应至关重要的功能。因此，小分子信号是 有吸引力的反感染者的目标。鉴于肠道的化学复杂性，微生物病原体 串扰必须很普遍。实际上，我们以前证明了人类粪便的有机提取物 在肠沙门氏菌中引起明显的转录反应，约有100个调控基因。有趣的是， 在被提取物抑制的人中，毒力基因很丰富，表明微生物群衍生 代谢物可以抑制毒力。然后，我们确定一个单一的共同肠肠citroniae， 可以抑制肠链球菌毒力基因表达。最近，我们研究了 其他病原体的人类粪便代谢组。在霍乱弧形霍乱弧菌中 效应更加明显，调节了约900个基因。运动是主要类别 抑制基因，并通过表型测定确认了效果。与肠道S. enterica一样，效果可能 用大肠杆菌概括。鉴于霍乱弧菌作为人类病原体的重要性和关键 运动在发病机理中扮演的角色，我们的目标是确定微生物群的影响 V.霍乱致病性的代谢产物。我们将产生具有抗动力的肠道分子的集合 表征生物活性的遗传和化学性质的特性。基因组和转录组 将比较主动菌株和非活性菌株，从而深入了解所涉及的合成设备。 将进行生物活性引导的纯化，并使用质谱法进行复合表征 和核磁共振将发生。最后，我们将研究主动菌株和化合物的影响 使用感染模型对宿主对霍乱弧菌的抗性。这项工作的结果将阐明化学物质 微生物菌 - 病原体相互作用的生物学，可能揭示具有潜在治疗的菌株和化合物 申请。