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

项目总结 感染性腹泻仍然是儿童发病率和死亡率的主要原因，免疫功能受损。 世界各地的患者。然而，缺乏与人类相似的新生儿和免疫缺陷动物模型 这些高度易感的患者群体的感染限制了我们对这种疾病的了解。因此，我们 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。 轮状柠檬酸杆菌肠道和全身感染的致病机制及宿主免疫的研究 和鼠伤寒沙门氏菌。 我们的第一个假设是，轮状芽胞杆菌使用不同的毒力因子来诱导致命的系统感染。 与最初肠道定植所需的相比，新生小鼠的肠道定植能力更强。《特定目标1》旨在 确定和表征新生儿菌血症建立所需的重要致病因素 使用全基因组筛选和体内功能研究(1A-C)。具体目标2将针对我们的第二个目标 关于免疫球蛋白对新生儿和成人肠道疾病的保护作用的假说，以及 在没有免疫球蛋白(2A-C)的情况下存在病原体根除的代偿或替代机制。 对轮状芽胞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 了解感染过程中微生物致病机制和宿主免疫的一般和特殊方面 易感个体(一维和二维)。这些研究具有很高的临床意义，因为它们可能提供新的 儿童和适应性减退患者肠道和全身疾病发病机制的研究 免疫，这与国家过敏和传染病研究所(NIAID)的目标非常一致。 此外，我们还制定了健全和全面的职业发展和培训计划， 将提供关于感染、粘膜和适应性免疫、病理学和免疫的替代模式的科学培训 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和 肠道内的炎症环境。该计划还将发展和加强基本的关键专业技能 成功领导独立研究计划，包括指导和教学方面的培训，科学 通信、联网、赠款准备和实验室管理。一群高素质的 知名科学家将指导和评估申请者为实现其科学和职业目标所做的努力。 总之，本提案中概述的研究和职业发展活动以及突出的 密歇根大学的制度环境将为PI追求独立的职业生涯做好充分准备 在以健康为导向的研究中，将他定位为细菌发病机制、宿主领域的一名强大的初级教员 免疫和宿主与病原体的相互作用。

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.