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

慢性沙门氏菌感染中肉芽肿巨噬细胞极化和肉芽肿形成的剖析机制

• 批准号: 10321557
• 负责人: Trung Hoang Minh Pham
• 金额: $ 19.43万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-17 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321557
• 关键词: Affect; Automobile Driving; Bacteria; Bacterial Infections; Bone Marrow; CRISPR/Cas technology; Cells; Cellular Immunity; Cellular Immunology; Cessation of life; Childhood; Chronic; Clinical; Communicable Diseases; Complex; Critical Pathways; Data; Development; Development Plans; Diagnostic; Disease; Disease Progression; Exhibits; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Goals; Granuloma; Heterogeneity; Image; Immune; Immune response; Immunology; Individual; Infection; Infection Control; Inflammatory Response; Integration Host Factors; Lead; Link; Maintenance; Mammalian Genetics; Mediating; Mentors; Microbiology; Modality; Modeling; Molecular; Monitor; Morphology; Multiplexed Ion Beam Imaging; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathologic; Pathway interactions; Persons; Phenotype; Physicians; Proteins; Regulation; Reporter; Research; Resolution; Risk; Role; Salmonella; Salmonella enterica; Salmonella infections; Salmonella typhimurium; Scientist; Signal Transduction; Spleen; System; T-Lymphocyte; TNF gene; Techniques; Therapeutic; Time; Tissues; Training; Type III Secretion System Pathway; Universities; Virulence Factors; Virulent; bacterial genetics; burden of illness; career; career development; chronic infection; experience; experimental study; genetic manipulation; imaging platform; in vivo; innovation; instructor; macrophage; mutant; novel; novel diagnostics; novel therapeutics; pathogen; pathogen exposure; pediatric department; therapeutic development; transcriptome sequencing

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.

项目摘要 细胞内的细菌，最值得注意的是沙门氏菌和结核分枝杆菌，感染数百个 每年造成数百万人死亡。这些病原体可以建立慢性感染， 在宿主组织中长期存活。在慢性期，许多感染者没有症状，但他们可以 发展为活动性疾病。目前，缺乏有效的战略来监测和调整 慢性细菌感染的疾病进展、再激活风险和治疗反应性。一个关键 许多细胞内细菌感染的共同病理特征是肉芽肿，这是一种复杂且动态的 组织微结构包括免疫细胞，特别是巨噬细胞和病原体。肉芽肿 形成被认为是控制感染的重要免疫反应，但它也是关键的免疫反应。 病原体持续存在的机制。我们的长期目标是确定肉芽肿的共同途径 这将导致慢性细菌性肺炎的诊断和治疗方式的根本性进展， 感染.在目前的建议中，我们将采取多管齐下的方法来剖析宿主的机制， 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， 我们将明确一个关键的宿主因子调节肉芽肿形成和细菌感染的机制。 坚持不懈目的2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，包括 基因工程小鼠和基因工程沙门氏菌来表征发育， 维持肉芽肿巨噬细胞。 拟议的研究是指导性职业发展计划的一部分，以使候选人获得 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。该候选人目前是一名教员， 斯坦福大学儿科传染病系。拟议的研究吸引了 根据候选人在细胞免疫学，细菌发病机制和临床感染性疾病方面的经验。 连同计划的教学和技术培训，概述的实验将为候选人提供一个 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，以及计算和系统免疫学， 他的主要导师，丹尼斯·莫纳克博士，和一个领先的医生科学家顾问团队。