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）：本研究项目的目的是确定细菌毒力因子和巨噬细胞宿主反应，这些因子是严重的播散性沙门氏菌感染的基础。非伤寒沙门氏菌是常见的食源性疾病的原因，传播性感染导致大量的发病率和死亡率。我们对沙门氏菌如何产生肠外疾病的理解是有限的。该项目的重点是人类巨噬细胞和2个主要沙门氏菌位点的蛋白质产物之间的宿主-病原体相互作用：spv位点，传播的关键毒力决定因素，和沙门氏菌致病岛，SPI-2。spv操纵子编码SpvB蛋白，一种修饰肌动蛋白单体的腺苷三磷酸转移酶。SPI-2编码细菌III型分泌系统，当沙门氏菌在细胞内时特异性活性。具体目的是：1）确定沙门氏菌诱导人巨噬细胞毒性所需的细菌毒力基因。2）分析细菌效应物诱导细胞凋亡的机制。3）研究巨噬细胞吞噬沙门氏菌时Toll样受体（TLR）信号转导及其对丝裂原活化蛋白激酶（MAPK）通路的影响。假设是在吞噬作用中，沙门氏菌脂多糖（LPS）触发TLR-4介导的细胞信号传导途径，刺激p38 MAPK，引起细胞凋亡的初始抑制。这使得生物体有时间在细胞内增殖。然后SpvB分泌分解细胞肌动蛋白，并启动程序性细胞死亡。这触发了细胞表面定位标记，用于其他未感染的巨噬细胞的吞噬作用，促进沙门氏菌的传播。我的长期目标是获得全职学术任命，对病原体进化以克服巨噬细胞先天免疫反应的分子遗传机制进行独立研究。该项目概述，在UCSD导师的指导下，并辅以研究生课程，将提供细菌分子遗传学，信号转导分析和巨噬细胞中的细胞凋亡的培训。

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