Salmonella-induced Cytopathology in Human Macrophages

沙门氏菌诱导的人巨噬细胞的细胞病理学

• 批准号: 7622093
• 负责人: SARA H. BROWNE
• 金额: $ 12.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7622093
• 关键词: Actins; Animals; Apoptosis; Apoptosis Regulator; Apoptotic; Appointment; Area; Bacteria; Bacterial Proteins; Bacterial Typing; Binding; C-terminal; Cell surface; Cells; Cytopathology; Cytoplasm; Cytoskeleton; Disease; Equilibrium; Equus caballus; F-Actin; Family; G Actin; Genes; Genetic; Goals; Growth; Human; Immune response; Infection; Inhibition of Apoptosis; Intestinal Diseases; Laboratories; MADHIP gene; Macrophage Activation; Mediating; Mentors; Microfilaments; Mitochondria; Mitogen-Activated Protein Kinases; Molecular Genetics; Morbidity - disease rate; Operon; Organism; Pathogenesis; Pathogenicity Island; Pathway interactions; Phagocytosis; Play; Proliferating; Protein Secretion; Proteins; Receptor Signaling; Research; Research Personnel; Research Project Grants; Role; Salmonella; Salmonella infections; Signal Pathway; Signal Transduction; Signal Transduction Pathway; System; Systemic infection; Testing; Time; Toll-like receptors; Training; Transferase; Type III Secretion System Pathway; Typhoid Fever; Vacuole; Virulence; Virulence Factors; Work; cytotoxic; cytotoxicity; depolymerization; foodborne illness; human MAPK14 protein; immune function; insight; macrophage; member; mitogen-activated protein kinase p38; monomer; mortality; novel; pathogen; polymerization; programs; toll-like receptor 4

DESCRIPTION (provided by applicant): The goal of this research project is to define the bacterial virulence factors and macrophage host responses underlying serious, disseminated Salmonella infection. Non-typhoid Salmonella are common causes of food born illness, disseminated infection causes substantial morbidity and mortality. Our understanding of how Salmonella produces extra-intestinal disease is limited. This project focuses on the host-pathogen interaction between human macrophages and the protein products of 2 major Salmonella loci: the spv locus, a critical virulence determinant of dissemination, and the Salmonella Pathogenicity Island, SPI-2. The spv operon encodes SpvB protein, an ADPribosyl transferase, which modifies actin monomers. SPI-2 encodes a bacterial type III secretion system specifically active when Salmonella are intracellular. The specific aims are: 1)To define bacterial virulence genes required for Salmonella-induced cytotoxicity in human macrophages. 2)To analyse the mechanisms bacterial effectors use to induce this cytopathology, including apoptosis. 3)To determine the Toll-like receptor (TLR) signaling and effect on Mitogen Activated Protein Kinase (MAPK) pathways when macrophages phagocytose Salmonella. The hypothesis is that on phagocytosis, Salmonella lipopolysaccaride (LPS) triggers a TLR-4 mediated cell signaling pathway, stimulating p38 MAPK, causing initial inhibition of apoptosis. This allows time for the organism to proliferate, intracellularly. SpvB secretion then breaks down cellular actin, and programmed cell death is initiated. This triggers cell surface localization markers, for phagocytosis by other uninfected macrophages, facillitating Salmonella spread. My long term objective is to gain a full-time academic appointment to conduct independent research on molecular genetic mechanisms pathogens have evolved to over come macrophages innate immune responses. The project outlined, guided by mentors at UCSD and supplemented by graduate courses, will provide training in bacterial molecular genetics, signal transduction analysis, and apoptsis in macrophages.

描述（由申请人提供）：该研究项目的目的是定义严重，散布沙门氏菌感染的细菌毒力因子和巨噬细胞宿主反应。非细类沙门氏菌是食物出生疾病的常见原因，传播感染会导致大量发病率和死亡率。我们对沙门氏菌如何产生肠外疾病的理解受到限制。该项目的重点是人类巨噬细胞与2个主要沙门氏菌基因座的蛋白质产物之间的宿主 - 病原体相互作用：SPV基因座，一个关键的传播决定因素，以及沙门氏菌致病岛，SPI-2。 SPV操纵子编码SPVB蛋白，一种adpribosyl转移酶，可修饰肌动蛋白单体。 SPI-2编码一型细菌III型分泌系统，当时沙门氏菌是细胞内的。具体目的是：1）定义沙门氏菌诱导的人类巨噬细胞中细胞毒性所需的细菌毒力基因。 2）分析细菌效应子用于诱导这种细胞病理学的机制，包括凋亡。 3）确定巨噬细胞吞噬沙门氏菌时的Toll样受体（TLR）信号传导以及对有丝分裂原活化蛋白激酶（MAPK）途径的影响。假设是，在吞噬作用上，沙门氏菌脂多亚甲酯（LPS）触发TLR-4介导的细胞信号传导途径，刺激p38 mapk，从而引起初步抑制细胞凋亡。这样可以使生物体细胞内增殖。然后，SPVB分泌分解细胞肌动蛋白，并开始编程的细胞死亡。这会触发细胞表面定位标记，用于其他未感染的巨噬细胞吞噬作用，可散布沙门氏菌。我的长期目标是获得全日制的学术任命，以对病原体的分子遗传机制进行独立研究，从而演变为巨噬细胞天生的免疫反应。该项目在UCSD的指导下概述并由研究生课程补充，将在巨噬细胞中提供细菌分子遗传学，信号转导分析和apoptsis的培训。

项目成果

Penetration and activation of brain endothelium by Salmonella enterica serovar Typhimurium.

• DOI: 10.1093/infdis/jiq048
• 发表时间: 2011-02
• 期刊: The Journal of infectious diseases
• 作者: N. V. van Sorge;Patricia Zialcita;S. Browne;Darin F. Quach;D. Guiney;K. Doran