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

基本信息

批准号：
10370045
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
项目类别：
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/10370045
关键词：
Acute Acute Diarrhea Address 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 Memory Immunology Impairment In Vitro Individual Infant Infection Inflammation Inflammatory 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 Preparation Public Health 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

项目摘要

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.

项目概要感染性腹泻仍然是儿童和免疫功能低下者发病和死亡的主要原因然而，缺乏与人类密切相关的新生儿和免疫缺陷动物模型。这些高度易感患者群体的感染限制了我们对这种疾病的了解。在此建议使用新型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过程中发病机制和宿主免疫的研究和鼠伤寒沙门氏菌血清型。我们的第一个假设是啮齿类柠檬酸杆菌利用不同的毒力因子来诱导致命的全身感染与初始肠道定植所需的新生小鼠相比，特定目标 1 被设计为识别和表征新生儿菌血症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) 将解决我们的第二个目标。关于 IgG 在新生儿和成人肠道中对抗肠道疾病的保护作用的假设，以及在缺乏 IgG 的情况下，存在补偿性或替代性的病原体根除机制 (2A-C)。啮齿类弯曲杆菌的研究结果将在人类病原体鼠伤寒沙门氏菌中进行测试，以允许更广泛的研究了解感染过程中微生物发病机制和宿主免疫的一般和具体方面这些研究具有很高的临床意义，因为它们可能提供新颖的结果。深入了解儿童和适应性受损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，我们还制定了稳健而全面的职业发展和培训计划，将提供关于感染的替代模型、粘膜和适应性免疫、病理学和疾病进展、高通量数据分析和评估细胞状态的最先进技术该计划还将发展和加强关键的专业技能。成功领导独立研究项目，包括指导和教学、科学方面的培训沟通、网络、资助准备和实验室管理等方面的高素质人才。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，以及杰出的密歇根大学的制度环境将为PI追求独立职业生涯做好充分准备在以健康为导向的研究中，他被定位为细菌发病机制领域的一名实力雄厚的初级教师，主持人免疫和宿主-病原体相互作用。