Deciphering the pathogenesis of an enteric pathogen in neonatal and immunodeficient mice

破译新生小鼠和免疫缺陷小鼠肠道病原体的发病机制

• 批准号: 10682377
• 负责人: Gustavo Caballero Flores
• 金额: $ 10.56万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-11 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682377
• 关键词: Acute; Acute Diarrhea; Adult; Affect; Animal Disease Models; Animal Model; Animals; Award; Bacteremia; Bacteria; Bioinformatics; Biological Assay; Candidate Disease Gene; Cells; Child; Chronic; Citrobacter rodentium; Communication; Cytometry; Data Analyses; Diarrhea; Disease; Disease Progression; Disease model; Educational process of instructing; Enteral; Environment; Escherichia coli EHEC; Faculty; Genes; Genetic; Goals; Grant; Health; Host Defense; Human; Immune; Immune response; Immunity; Immunocompetent; Immunocompromised Host; Immunodeficient Mouse; Immunoglobulin G; Immunoglobulins; Immunologic Deficiency Syndromes; Immunologic Memory; Immunology; Impairment; In Vitro; Individual; Infant; Infection; Inflammation; Inflammatory; Institution; Intestinal Diseases; Intestines; Laboratories; Lead; Life Style; Mentors; Michigan; Modeling; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mus; Mutant Strains Mice; Mutation; National Institute of Allergy and Infectious Disease; Neonatal; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Positioning Attribute; Predisposition; Preparation; Public Health; Qualifying; Research; Role; Salmonella; Salmonella typhimurium; Scientist; Study models; Systemic disease; Systemic infection; Techniques; Technology; Testing; Training; Universities; Virulence; Virulence Factors; adaptive immunity; bacterial genetics; career; career development; chronic infection; clinically relevant; clinically significant; complement C2a; design; enteric infection; enteric pathogen; enteropathogenic Escherichia coli; genome wide screen; gut colonization; human pathogen; immunodeficient mouse model; in vivo; inflammatory milieu; insight; intestinal barrier; intestinal homeostasis; mature animal; microbial; mortality; mouse model; neonatal mice; neonate; novel; pathogen; pediatric patients; programs; protective effect; pup; research and development; single-cell RNA sequencing; skills; tissue repair; transposon sequencing

Project summary Infectious diarrhea remains a leading cause of morbidity and mortality in children and immunocompromised patients worldwide. However, the lack of neonatal and immunodeficient animal models that closely mirror human infection in these highly susceptible patient groups has limited our understanding of the disease. Therefore, we propose here the use of novel neonatal and immunodeficient mouse models of disease to study the mechanisms of pathogenesis and host immunity during enteric and systemic infection by the pathogens Citrobacter rodentium and Salmonella enterica serovar Typhimurium. Our first hypothesis is that C. rodentium employs different virulence factors to induce lethal systemic infection in neonatal mice compared to those required for initial intestinal colonization. Specific Aim 1 was designed to identify and characterize significant pathogen factors required for the establishment of bacteremia in neonates using genome-wide screens and functional studies in vivo (1A-C). Specific Aim 2 will address our second hypothesis regarding the protective role of IgG against enteric disease both in the neonatal and adult gut, and the existence of compensatory or alternative mechanisms of pathogen eradication in the absence of IgG (2A-C). Findings obtained with C. rodentium will be tested in the human pathogen S. Typhimurium to allow a broader understanding of the general and specific aspects of microbial pathogenesis and host immunity during infection in susceptible individuals (1D & 2D). These studies have high clinical significance as they may provide novel insight into the pathogenesis of enteric and systemic disease both in children and patients with impaired adaptive immunity, which aligns well with the goals of the National Institute of Allergy and Infectious Diseases (NIAID). Additionally, we have also developed a robust and comprehensive career development and training plan that will provide scientific training in alternative models of infection, mucosal and adaptive immunity, pathology and disease progression, high-throughput data analysis, and state-of-the-art technologies to assess cell state and inflammatory environment in the gut. This plan will also develop and strengthen key professional skills essential to successfully lead an independent research program, including training in mentoring and teaching, scientific communication, networking, grant preparation, and laboratory management. A group of highly qualified and renowned scientists will guide and evaluate the applicant’s efforts to achieve his scientific and career goals. Altogether, the research and career development activities outlined in this proposal, along with the outstanding institutional environment at the University of Michigan, will fully prepare the PI to pursue an independent career in health-oriented research, positioning him as a strong junior faculty in the fields of bacterial pathogenesis, host immunity and host-pathogen interactions.

项目摘要 感染性腹泻仍然是儿童发病率和死亡率的主要原因， 全世界的患者。然而，缺乏与人类免疫缺陷动物模型相似的新生儿和免疫缺陷动物模型， 这些高度敏感的患者群体的感染限制了我们对疾病的了解。所以我们 我在这里建议使用新的新生儿和免疫缺陷小鼠疾病模型来研究其机制 啮齿类柠檬酸杆菌肠道和全身感染的致病机制和宿主免疫 和鼠伤寒沙门氏菌。 我们的第一个假设是C。啮齿动物利用不同的毒力因子诱导致死性全身感染 与初始肠道定植所需的那些相比，新生小鼠中。具体目标1旨在 确定和表征新生儿菌血症建立所需的重要病原体因素 使用全基因组筛选和体内功能研究（1A-C）。具体目标2将解决我们的第二个 关于IgG对新生儿和成人肠道疾病的保护作用的假设，以及 在不存在IgG的情况下，存在病原体根除的补偿或替代机制（2A-C）。 结果表明，C.将在人类病原体S.鼠伤寒沙门氏菌允许更广泛的 了解感染期间微生物发病机制和宿主免疫的一般和具体方面 易感个体（1D和2D）。这些研究具有很高的临床意义，因为它们可以提供新的 了解儿童和适应障碍患者肠道和全身疾病的发病机制 免疫力，这与国家过敏和传染病研究所（NIAID）的目标非常一致。 此外，我们还制定了一个强大而全面的职业发展和培训计划， 将提供感染，粘膜和适应性免疫，病理学和 疾病进展、高通量数据分析和最先进的技术来评估细胞状态， 肠道炎症环境。该计划还将发展和加强关键的专业技能， 成功地领导一个独立的研究计划，包括在指导和教学，科学培训， 通信、网络、拨款准备和实验室管理。一批高素质、 著名科学家将指导和评估申请人为实现其科学和职业目标所做的努力。 总而言之，本提案中概述的研究和职业发展活动，沿着突出的 密歇根大学的制度环境，将充分准备PI追求独立的职业生涯 在以健康为导向的研究，定位他作为一个强大的初级教师在细菌发病机理，主机等领域， 免疫和宿主-病原体相互作用。