Dissecting Mechanisms of Granuloma Macrophage Polarization and Granuloma Formation in Chronic Salmonella Infection

项目概要 细胞内细菌，尤其是肠沙门氏菌和结核分枝杆菌，可感染数百种细菌。 每年造成数百万人死亡。这些病原体可以造成慢性感染 在宿主组织内长期存活。在慢性阶段，许多感染者没有症状，但他们可以 发展为活动性疾病。目前缺乏有效的监测和调节策略 慢性细菌感染的疾病进展、再激活风险和治疗反应。一把钥匙 许多细胞内细菌感染的共同病理特征是肉芽肿，这是一种复杂的、动态的 由免疫细胞（特别是巨噬细胞）和病原体组成的组织微观结构。肉芽肿 形成被认为是控制感染的重要免疫反应，但它也是至关重要的 病原体持续存在的机制。我们的长期目标是确定肉芽肿的常见途径 的形成将导致慢性细菌的诊断和治疗方式的根本性进步 感染。在当前的提案中，我们将采取多管齐下的方法来剖析主机的机制。 病原体相互作用支持肉芽肿形成和慢性沙门氏菌感染的控制。在目标 1 中， 我们将定义关键宿主因子调节肉芽肿形成和细菌的机制 坚持。目标 2 的目标是确定肉芽肿形成的关键途径 新型沙门氏菌毒力因子。在目标 3 中，我们建议构建一个创新的报告系统，其中包括 基因工程小鼠和基因工程沙门氏菌来表征发育和 维持肉芽肿巨噬细胞。 拟议的研究是指导候选人职业发展计划的一部分，以获得 独特的跨学科技能，以实现研究宿主病原体的独立学术研究生涯 细菌感染发病机制中的相互作用。该候选人目前是该部门的讲师 斯坦福大学儿科小儿传染病。 The proposed research draws 根据候选人在细胞免疫学、细菌发病机制和临床传染病方面的经验。 连同计划的教学和技术培训，概述的实验将为候选人提供 框架以获得新的专业知识领域，包括分子微生物学和细菌遗传学、切割 边缘哺乳动物遗传操作技术，以及以计算和系统免疫学为代表的技术 他的主要导师 Denise Monack 博士以及领先的医师科学家顾问团队。

Project summary Intracellular bacteria, most notably, Salmonella enterica and Mycobacterium tuberculosis, infect hundreds of millions of people and cause millions of deaths annually. These pathogens can establish chronic infections to survive long-term within host tissues. In chronic stage, many infected individuals are asymptomatic, but they can progress to develop active disease. Currently there is a paucity of effective strategies to monitor and modulate disease progression, reactivation risks, and therapy responsiveness for chronic bacterial infections. A key pathological feature common to many intracellular bacterial infections is granuloma, a complex and dynamic tissue microstructure comprised of immune cells, particularly macrophages, and pathogens. Granuloma formation is thought to be an important immune response to control infection, but it also serves as a crucial mechanism for pathogen persistence. Our long-term goal is to identify common pathways involved in granuloma formation that would lead to fundamental advances in diagnostic and therapeutic modalities for chronic bacterial infections. In the current proposal, we will take multipronged approaches to dissect mechanisms of host- pathogen interactions underpinning granuloma formation and control of chronic Salmonella infection. In Aim 1, we will define the mechanisms by which a critical host factor regulates granuloma formation and bacterial persistence. The objective of Aim 2 is to identify the key pathways of granuloma formation manipulated by a novel Salmonella virulence factor. In Aim 3, we propose to construct an innovative reporter system consisting of genetically engineered mice and genetically engineered Salmonella to characterize development and maintenance of granuloma macrophages. The proposed research is a component of a mentored career development plan for the candidate to acquire a unique interdisciplinary skillset to achieve an independent academic research career studying host-pathogen interactions in the pathogenesis of bacterial infections. The candidate is currently an Instructor in the Division of Pediatric Infectious Diseases, Department of Pediatrics, at Stanford University. The proposed research draws upon the candidate’s experience in cellular immunology, bacterial pathogenesis, and clinical infectious diseases. Together with planned didactics and technical training, the experiments outlined will provide the candidate a framework to acquire new domains of expertise including molecular microbiology and bacterial genetics, cutting- edge mammalian genetic manipulation techniques, and computational and systems immunology represented by his primary mentor, Dr. Denise Monack, and a team of leading physician-scientist advisors.