ERIN CRC: Host-microbiota-pathogen interactions govern enteric health and disease

ERIN CRC：宿主-微生物群-病原体相互作用控制肠道健康和疾病

• 批准号: 8125061
• 负责人: LINDA S. MANSFIELD
• 金额: $ 148.47万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8125061
• 关键词: ERIN; CRC; Host; microbiota; pathogen

DESCRIPTION (provided by applicant): The Michigan State University Enterics Research Investigational Network, Cooperative Research Center (MSU ERIN CRC) is a multidisciplinary Research Center proposal to study the enteric microbiome in health and disease with the overarching objective to elucidate its relationship to one of the most important global health problems, diarrheal illness. MSU ERIN CRC is a synergistic group of scientists from multiple disciplines, including microbial ecology, microbiology, immunology, epidemiology, and engineering, with cooperation from physicians working in infectious diseases, surgery, and pediatrics. Our long term goal is to determine the role of the microbiome in enhancing susceptibility or providing resistance to enteric diseases. We will focus on relationships between factors mediating diarrheal disease: enteric bacterial pathogens, the enteric microbiome, and host responses controlling susceptibility, resistance, or autoimmunity. Our overarching hypotheses are: (1) the enteric microbiome protects the host from luminal, epithelial and invasive pathogens, (2) diversity of the microbiome controls resiliency after perturbations, (3) the community metabolome contributes to lesions during pathogen invasion, and (4) resident microbiota intensify autoimmune responses by bacterial motifs exhibiting molecular mimicry. We will address these hypotheses using (1) bioreactors and mice colonized with human microbiota in Areas 1 and 2, and (2) samples from an epidemiological study of laboratory-confirmed cases of diarrhea in Area 3. In Area 1, Microbial Ecology and Pathogenesis, our overall objectives are to determine if (1) reduced diversity of the intestinal microbial community allows enteric pathogens with different lifestyles (luminal, epithelium-associated, and invasive) to become established in human fecal microbial communities in bioreactors and humanized mice, and (2) if the general ecological principle of competitive exclusion governs this process. In Area 2, Host Response, our overall objectives are to determine if murine model(s) with a "humanized" microbiome will develop spontaneous autoimmune sequelae secondary to C. jejuni infection with class A LOS; these models will then be used to dissect mechanisms of autoimmunity and to serve as treatment and prevention surrogates for GBS/MFS patients. In Area 3, Clinical Research, our overall objectives are to determine if shifts in the intestinal microbiome that increase host susceptibility to enteric disease are associated with (1) loss or inhibition of community members that negatively impact activities of an enteric pathogen, or (2) loss or inhibition of community members that interact with the host to promote resistance to enteric pathogens.

描述（由申请人提供）：密歇根州立大学进入研究中心（MSU ERIN CRC）是一项多学科研究中心的建议，旨在研究健康和疾病的肠道微生物组，其总体目的是阐明其与最重要的全球健康问题之一的关系，腹部疾病。 MSU Erin CRC是来自多个学科的科学家组成的协同群体，包括微生物生态学，微生物学，免疫学，流行病学和工程学，以及从事传染病，手术和儿科的医生的合作。我们的长期目标是确定微生物组在增强易感性或为肠道疾病提供抵抗力方面的作用。我们将重点关注介导腹泻病的因素之间的关系：肠细菌病原体，肠道微生物组和宿主反应，以控制易感性，耐药性或自身免疫性。 Our overarching hypotheses are: (1) the enteric microbiome protects the host from luminal, epithelial and invasive pathogens, (2) diversity of the microbiome controls resiliency after perturbations, (3) the community metabolome contributes to lesions during pathogen invasion, and (4) resident microbiota intensify autoimmune responses by bacterial motifs exhibiting molecular模仿。我们将使用（1）在1和2区与人类微生物群定殖的生物反应器和小鼠以及（2）在1区域3。区域第3区的腹泻病例的样本中解决这些假设。 （Luminal，上皮相关和侵入性）在生物反应器和人源性小鼠的人类粪便微生物群落中建立，并且（2）如果竞争性排斥的一般生态原理控制这一过程。在区域2（宿主反应）中，我们的总体目标是确定具有“人性化”微生物组的鼠模型是否会产生自发自身免疫后遗症继发于C. jejuni感染了A类LOS；然后，这些模型将用于剖析自身免疫的机制，并作为GBS/MFS患者的治疗和预防替代物。在第3区，临床研究中，我们的总体目标是确定增加肠道微生物组的变化是否增加了宿主对肠道疾病的易感性的转移与（1）（1）丧失或抑制社区成员的丧失或抑制肠病病原体的活动，或（2）与宿主相互作用以促进肠胃病原体的耐药性的损失或抑制。