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

项目总结 细胞内的细菌，最著名的是肠沙门氏菌和结核分枝杆菌，感染了数百 每年有数百万人死亡，并造成数百万人死亡。这些病原体可以建立慢性感染以 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 发展活动性疾病的进展。目前，缺乏有效的战略来监测和调节 慢性细菌感染的疾病进展、再激活风险和治疗反应性。一把钥匙 许多细胞内细菌感染的共同病理特征是肉芽肿，这是一种复杂和动态的 组织微结构由免疫细胞，特别是巨噬细胞和病原体组成。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 病原菌持续存在的机制。我们的长期目标是确定肉芽肿的共同途径。 将导致慢性细菌诊断和治疗方式的根本进步的形成 感染。在目前的提案中，我们将多管齐下剖析宿主的机制-- 支持肉芽肿形成和控制慢性沙门氏菌感染的病原体相互作用。在目标1中， 我们将确定一个关键的宿主因子调节肉芽肿形成和细菌的机制。 坚持不懈。目标2的目标是确定肉芽肿形成的关键途径。 沙门氏菌新毒力因子。在目标3中，我们建议构建一个创新的记者制度，包括 转基因小鼠和转基因沙门氏菌以表征发育和 肉芽肿巨噬细胞的维持。 建议的研究是指导职业发展计划的一部分，供候选人获得 独特的跨学科技能，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。应聘者目前是以下部门的讲师 斯坦福大学儿科教研室儿科传染病。这项拟议的研究得出了 根据应聘者在细胞免疫学、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，概述的实验将为应聘者提供 框架，以获得新的专业领域，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 他的主要导师丹尼斯·莫纳克博士和一支由领先的内科科学家顾问组成的团队。

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.