Microbial Metabolites Inhibiting Salmonella Carriage and Disease

抑制沙门氏菌携带和疾病的微生物代谢物

• 批准号: 10645214
• 负责人: CRAIG ALTIER
• 金额: $ 38.4万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-14 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645214
• 关键词: Acids; Affect; Affinity; Animal Model; Animals; Bacteria; Bacterial Adhesins; Bacterial Infections; Behavior; Binding; Biochemical; Biological Assay; Biological Process; Biological Response Modifier Therapy; Carbon; Cause of Death; Cell Adhesion; Characteristics; Chemicals; Complex; Development; Disease; Energy-Generating Resources; Enoyl-CoA Hydratase; Environment; Epithelial Cells; Equilibrium; Ethanolamines; Excretory function; Fatty Acids; Gene Expression; Genes; Genetic; Goals; Gram-Negative Bacteria; Human; Infection; Intestines; Invaded; Large Intestine; Macrophage; Measures; Metabolic; Molecular; Mus; Nutrient; Organ; Organism; Outcome Study; Phenotype; Population; Positioning Attribute; Problem Sets; Proliferating; Public Health; Regulon; Repression; Salmonella; Salmonella infections; Signal Transduction; Source; System; Testing; Transcription Coactivator; Virulence; Work; combat; cost; enteric pathogen; fitness; foodborne; gene function; gut colonization; gut microbiome; gut microbiota; human disease; human model; improved; in vivo; innovation; intestinal epithelium; long chain fatty acid; member; microbial; microbiota; microbiota metabolites; mouse model; novel; novel therapeutics; pathogen; pi bond; prevent; quorum sensing; response; tool

ABSTRACT Diffusible signal factors (DSFs), long-chain fatty acids with a characteristic cis-2 unsaturation, are produced and used by several genera of gram-negative bacteria as quorum-sensing signals. We have found that the DSF cis-2 hexadecenoic acid (c2-HDA) is extremely potent in inhibiting expression of Salmonella functions necessary for colonization of the intestine and have found this compound to be present in the murine large intestine. As no mammalian source of fatty acids harboring a 2-cis unsaturation has been described, these findings strongly suggest that constituents of the gut microbiota produce and excrete DSFs that inhibit Salmonella virulence. We hypothesize that Salmonella uses the signals of these bacteria to balance its virulence functions, essential but also costly to the fitness and survival of the invading bacteria, with colonization and proliferation of the Salmonella population. Gut microbial metabolites may therefore serve multiple coordinated purposes in pathogens, balancing virulence functions with those required for proliferation within a host and thus affecting pathogen survival in the gut by multiple means. Here we propose to: Aim 1: Use complementary approaches to identify bacteria of the human gut microbiome that produce inhibitory DSFs and characterize their products; Aim 2: Identify the constellation of functions regulated in Salmonella by DSFs and identify mechanisms of this control, and; Aim 3: Using established murine models of Salmonella infection, characterize the biological function and translational relevance of c2-HDA to understand its mechanism of action and to support the eventual development of novel therapeutics, such as live biotherapeutic products, for the control of human salmonellosis.

摘要 产生扩散信号因子(DSFs)，即具有顺式-2不饱和度特征的长链脂肪酸 并被几个属的革兰氏阴性细菌用作群体感应信号。我们发现， DSF顺式-2十六碳烯酸(c2-hda)对沙门氏菌功能的表达具有极强的抑制作用 对肠道的定植是必要的，并发现这种化合物存在于小鼠的大肠 肠子。由于没有描述过含有2-顺式不饱和脂肪酸的哺乳动物来源，这些 研究结果有力地表明，肠道微生物区系的成分产生和排泄抑制DSFs 沙门氏菌毒力。我们推测沙门氏菌利用这些细菌的信号来平衡其 毒力功能，对入侵细菌的健康和生存至关重要，但也代价高昂， 沙门氏菌种群的定植和繁殖。因此，肠道微生物代谢物可能会 病原体的多个协调目的，平衡毒力功能和增殖所需的功能 在宿主内，从而通过多种方式影响病原体在肠道中的存活。在此，我们建议：目标1： 使用互补方法鉴定人体肠道微生物群中产生抑制性DSFs的细菌 目标2：确定沙门氏菌受DSFs调控的功能星座 并确定这种控制的机制，以及目标3：使用已建立的沙门氏菌感染的小鼠模型， 鉴定c2-HDA的生物学功能和翻译相关性，以了解其发病机制。 行动，并支持最终开发新的治疗方法，如活的生物治疗产品，用于 人类沙门氏菌病的控制。