Tolerance defenses in host-microbiota interactions

宿主-微生物群相互作用中的耐受性防御

• 批准号: 10594963
• 负责人: Janelle S Ayres
• 金额: $ 48.1万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-10 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594963
• 关键词: Acute; Adaptive Immune System; Address; Affect; Antibody Response; Attenuated; Behavior; Carbohydrates; Chronic; Citrobacter; Citrobacter rodentium; Colitis; Data; Defense Mechanisms; Disease; Enteral; Evolution; Glucose; Goals; Health; Host Defense; Immune response; Immunocompromised Host; Immunology; Individual; Infection; Infectious colitis; Inflammation; Intestines; Investigation; Iron; Lead; Lipids; Macronutrients Nutrition; Mediating; Metabolic; Metabolic Control; Metabolism; Microbe; Micronutrients; Modeling; Mucous Membrane; Mus; Outcome; Pathogenicity; Pathology; Pathway interactions; Phenotype; Physiological; Physiology; Process; Regulation; Research; Role; Starvation; Symbiosis; System; Virulence; Virulent; Work; adaptive immune response; attenuation; carbohydrate metabolism; dietary; enteric pathogen; fitness; gastrointestinal; glucose metabolism; gut microbiota; host microbiota; in vivo; lipid metabolism; member; microbial; microbial community; microbiota; mouse model; novel; pathogen; pathogenic bacteria; pathogenic microbe; prevent; programs; response; synergism; tool; transmission process

Project Summary The overall goal of this proposal is to understand how host metabolic adaptations during infection promote co- operative defenses between a host and enteric pathogens to drive asymptomatic carriage and the eventual evolution of commensalism. The proposed studies utilize a natural in vivo host-pathogen involving a enteric bacterial pathogen that causes infectious colitis. In previous work, the Ayres lab discovered that host micronutrient metabolic adaptations during infection with enteric pathogens, regulates host carbohydrate metabolism leading to a phenomenon the Ayres lab calls “metabolic bribery”. This involves the allocation of carbohydrates to the niche of the pathogen (intestine) to increase availability for the pathogen to metabolize. The Ayres lab discovered that the metabolism of these specific carbohydrates by the pathogen suppressed pathogen virulence and disease, indicating this micronutrient regulation of host and pathogen macronutrient metabolism acts as an anti-virulence mechanism. In the new proposal, the Ayres lab presents exciting data demonstrating that micronutrient metabolism coordinates interactions between host glucose and lipid metabolism to suppress virulence and promote cooperation with enteric pathogens. The proposed studies will investigate the mechanisms by which dietary micronutrients regulate macronutrient metabolism to suppress pathogen virulence to yield asymptomatic carriers of the pathogen. The proposed studies will focus on understanding how micronutrient metabolism orchestrates glucose and lipid processes in the body to suppress pathogen virulence. The proposed studies will then examine the interplay between the adaptive immune response and micronutrient mediated cooperative defenses, elucidating how these two systems cooperate to mediate healthy host-pathogen interactions and protect from infectious colitis. Finally, the proposed studies will utilize this novel host-pathogen/micronutrient system to elucidate the mechanisms that drive the evolution of pathogen attenuation towards commensalism and persistence within the microbiota. This work will contribute to a better understanding for gastrointestinal mucosal adaptive immunology, mechanisms of acute and chronic gastrointestinal inflammation and colitis, the effects of gastrointestinal microbes and microbial metabolism on gastrointestinal health and disease, including the effects of pathogenic bacterial pathogens.

项目摘要 该提案的总体目标是了解感染期间宿主的代谢适应如何促进共代谢， 宿主和肠道病原体之间的有效防御，以驱动无症状携带， 进化论。所提出的研究利用涉及肠毒素的天然体内宿主病原体。 引起传染性结肠炎的细菌病原体。在之前的工作中，艾尔斯实验室发现， 肠道病原体感染期间微量营养素代谢适应，调节宿主碳水化合物 这导致了艾尔斯实验室称之为“代谢贿赂”的现象。这涉及到分配 碳水化合物进入病原体的生态位（肠）以增加病原体代谢的可用性。 艾尔斯实验室发现，病原体抑制了这些特定碳水化合物的代谢， 病原菌的毒力和致病性，表明这种微量营养调控宿主和病原菌的大量营养 代谢作为抗毒性机制。在新的提案中，艾尔斯实验室提出了令人兴奋的数据， 证明微量营养素代谢协调宿主葡萄糖和脂质之间的相互作用 代谢抑制毒力和促进与肠道病原体的合作。拟议的研究将 研究膳食微量营养素调节宏量营养素代谢的机制， 病原体毒力产生病原体的无症状携带者。拟议的研究将侧重于 了解微量营养素代谢如何协调体内的葡萄糖和脂质过程， 病原体毒力拟议的研究将检查适应性免疫之间的相互作用， 反应和微量营养素介导的合作防御，阐明这两个系统如何合作， 介导健康的宿主-病原体相互作用并保护免受感染性结肠炎。最后，拟议的研究将 利用这种新的宿主-病原体/微量营养素系统来阐明驱动细菌进化的机制， 病原体衰减到微生物群内的寄生虫和持久性。这项工作将有助于 为了更好地了解胃肠道粘膜适应性免疫学，急性和慢性炎症的机制， 胃肠道炎症和结肠炎，胃肠道微生物和微生物代谢对 胃肠道健康和疾病，包括致病性细菌病原体的影响。