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: 10819069
• 负责人: Janelle S Ayres
• 金额: $ 7.79万
• 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/10819069
• 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代谢适应如何促进共同 宿主和肠道病原体之间的手术防御措施，以驱动不对称载体和最终 共生主义的演变。拟议的研究利用涉及进入的天然体内宿主病原 引起感染性结肠炎的细菌病原体。在以前的工作中，Ayres实验室发现了主机 肠道病原体感染过程中的微量营养素代谢适应，调节宿主碳氢化物 代谢导致现象艾尔斯实验室称为“代谢贿赂”。这涉及分配 碳水化合物到病原体（肠）的细分市场，以增加代谢的病原体的可用性。 Ayres实验室发现，这些特定的碳氢化物被病原体抑制的代谢 病原体病毒和疾病，表明对宿主和病原体大营养素的微量营养素调节 代谢充当抗病毒机制。在新提案中，Ayres实验室提出了令人兴奋的数据 证明微量营养素的代谢坐在宿主葡萄糖与脂质之间的相互作用 代谢抑制病毒并促进促进病原体的合作。拟议的研究将 研究饮食微量营养素调节大量营养素代谢的机制 病原体病毒可产生病原体的不对称载体。拟议的研究将重点放在 了解微量营养素的代谢如何在体内策划葡萄糖和脂质过程以抑制 病原体病毒。然后，提出的研究将检查自适应免疫之间的相互作用 反应和微量营养素介导的合作防御，阐明了这两个系统如何协调 媒体健康的宿主病原体相互作用并防止感染性结肠炎。最后，拟议的研究将 利用这种新型的宿主病原/微量营养素系统来阐明驱动驱动演变的机制 病原体衰减对微生物群中的共生和持久性。这项工作将做出贡献 可以更好地了解胃肠道粘膜适应性免疫学，急性和慢性的机制 胃肠道感染和结肠炎，胃肠道微生物和微生物代谢对 胃肠道健康和疾病，包括致病细菌病原体的作用。