Macrophages, Granulomas, and Bacterial Persistence

巨噬细胞、肉芽肿和细菌持久性

• 批准号: 9277403
• 负责人: Corrella S Detweiler
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277403
• 关键词: Acute; Address; Alpha Cell; Area; Bacteria; Bacterial Infections; Bone Marrow; Brucella abortus; Cell Survival; Characteristics; Chemicals; Chronic; Chronic Disease; Clinical; Data; Development; Erythrocytes; Food Contamination; Genetic; Goals; Granuloma; Growth; Hematopoietic; Host Defense; Human; Immune; Immune system; Immunocompetent; Inductively Coupled Plasma Mass Spectrometry; Infection; Inflammatory; Ingestion; Interferon Type II; Iron; Leishmania; Leukocytes; Lymphoid Tissue; Methods; Microbe; Modeling; Molecular; Mus; Mycobacterium leprae; Mycobacterium tuberculosis; Pathology; Pathway interactions; Phagocytes; Phase; Proteomics; Public Health; Relapse; Salmonella; Salmonella enterica; Salmonella typhimurium; Serotyping; Site; System; Systemic infection; Testing; Therapeutic; Tissues; Toxin; Typhoid Fever; alpha Toxin; antimicrobial; base; cell type; contaminated water; cytokine; experimental study; inhibitor/antagonist; macrophage; metal transporting protein 1; novel therapeutics; pathogen; uptake

Summary Salmonella enterica subspecies Typhimurium is a natural pathogen of mice that establishes persistent, systemic infection. Salmonella generally reside within professional phagocytes, typically macrophages, which is critical for the development of chronic infection. However, it is unclear how Salmonella can survive within a cell-type that evolved to destroy pathogens. Our lab has demonstrated that during persistent murine infections, S. Typhimurium can reside within macrophages that are hemophagocytic. Hemophagocytic macrophages (HMФs) are characterized by the ingestion of viable cells of the hematopoietic lineages, and are clinically associated with human Typhoid fever. We have also observed that by three weeks post-infection, activated macrophages, and possibly HMФs, coalesce into granulomas that harbor and appear to protect bacteria from the host immune system, potentially establishing a site at which the bacteria can survive long-term. The goal of this proposal is to determine how S. Typhimurium exploits macrophages, including HMФs and macrophages within granulomas, to withstand host defenses during acute and chronic infection. We are modeling HMФs and granulomas and the following two aims will address key questions regarding how bacteria establish and maintain colonization of tissues within HMФs and granulomas: 1) How does S. Typhimurium acquire iron from macrophages? and 2) How does S. Typhimurium survive in granulomas? How granulomas form and acquire and maintain bacteria such as Salmonella remains a poorly understood area that may be able to be targeted with therapeutics.

概括 肠沙门氏菌亚种鼠伤寒是小鼠的天然病原体，可建立持久的、系统性的 感染。沙门氏菌通常驻留在专业吞噬细胞（通常是巨噬细胞）内，这一点至关重要 发展为慢性感染。然而，尚不清楚沙门氏菌如何在细胞类型中生存 进化来消灭病原体。我们的实验室已经证明，在小鼠持续感染期间，S. 鼠伤寒杆菌可驻留在噬血细胞的巨噬细胞内。噬血细胞巨噬细胞 (HMФs) 其特征是摄入造血谱系的活细胞，并且在临床上与 人类伤寒。我们还观察到，感染后三周，巨噬细胞和 可能是 HMФ，合并成肉芽肿，并似乎可以保护细菌免受宿主免疫的影响 系统，有可能建立一个细菌可以长期生存的场所。该提案的目标是 确定鼠伤寒沙门氏菌如何利用巨噬细胞，包括肉芽肿内的 HMФ 和巨噬细胞， 在急性和慢性感染期间抵抗宿主的防御。我们正在对 HMФ 和肉芽肿进行建模 以下两个目标将解决有关细菌如何建立和维持定植的关键问题 HMФ 和肉芽肿内的组织： 1) 鼠伤寒沙门氏菌如何从巨噬细胞获取铁？和 2) 鼠伤寒沙门氏菌如何在肉芽肿中存活？肉芽肿如何形成、获得和维持 沙门氏菌等细菌仍然是一个人们知之甚少的领域，但这些领域可能能够成为治疗的目标。