Macrophages, Granulomas, and Bacterial Persistence

巨噬细胞、肉芽肿和细菌持久性

基本信息

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
项目类别：
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

项目摘要

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.

概括沙门氏菌肠typhimurium是小鼠的天然病原体，可以建立持续的全身性感染。沙门氏菌通常位于专业的吞噬细胞中，通常是巨噬细胞，这很关键为了发展慢性感染。但是，尚不清楚沙门氏菌如何在细胞类型中生存这进化为破坏病原体。我们的实验室证明，在持续的鼠感染期间，S。鼠伤寒可以驻留在造血细胞的巨噬细胞中。造血细胞巨噬细胞（HMOS）其特征是摄入造血谱系的活细胞，并在临床上与人伤寒。我们还观察到，感染后三周，激活的巨噬细胞和 HMS，合并为颗粒，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部位。该提议的目的是为了确定鼠伤寒链球菌如何利用巨噬细胞，包括肉芽肿内的HMS和巨噬细胞，在急性和慢性感染期间承受宿主防御。我们正在建模HMS和颗粒瘤以及以下两个目标将解决有关细菌如何建立和维持殖民化的关键问题 HMS和颗粒中的组织：1）鼠伤寒链球菌如何从巨噬细胞中获取铁？和 2）鼠伤寒链球菌如何在颗粒中生存？颗粒瘤如何形成，并获得和维护诸如沙门氏菌之类的细菌仍然是一个鲜为人知的区域，可能能够针对治疗。