Staphylococcus Aureus Activation of TNF Signaling Pathways

金黄色葡萄球菌激活 TNF 信号通路

基本信息

批准号：
8910776
负责人：
Alice S Prince
金额：
$ 39.06万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8910776
关键词：
Abbreviations Acute Acute Pneumonia Agonist Alveolar Cell Alveolar Macrophages Antibiotics Antigen-Presenting Cells Antigens Apoptosis Bacteria Biochemical Biological Preservation Bone Marrow Bronchoscopy CD28 gene CD4 Positive T Lymphocytes Caspase-1 Cell Communication Cell Death Cell Line Cell physiology Cells Cessation of life Clinical Colony-forming units Dendritic Cells Dichloromethylene Diphosphonate Epithelial Cells Family Gene Expression Health Hemolysin Human IL27RA gene Image Immune response In Situ In Vitro Infection Inflammation Inflammatory Inflammatory Response Knock-out Leucocidin Ligands Lung Macrophage Colony-Stimulating Factor Mediating Membrane Proteins Modeling Monocytic leukemia Mus Outcome Pathology Pathway interactions Patients Phagocytes Pharmaceutical Preparations Phenotype Pneumonia Population Process Proteins RIPK1 gene RIPK3 gene Reactive Oxygen Species Recruitment Activity Regulation Regulator Genes Regulatory T-Lymphocyte Relative (related person)Role Signal Pathway Signal Transduction Source Staphylococcal Protein A Staphylococcus aureus Superantigens T cell regulation T-Cell Activation T-Lymphocyte TNF gene Testing Tissues Toxin Tumor Necrosis Factor Receptor Virulence Virulence Factors airway epithelium cell type cytokine cytotoxicity genetic approach immune clearance improved inhibitor/antagonist killings macrophage methicillin resistant Staphylococcus aureus mutant neutrophil pathogen prevent receptor research study response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Staphylococcus aureus is a major human pathogen, associated with many types of infection including severe pneumonia. S. aureus activate multiple, often redundant proinflammatory signaling cascades in the lungs involving the airway epithelium as well as neutrophils, alveolar macrophages, dendritic cells and recruited T cells. While neutrophils are critical in the eradication of S. aureus, excessive proinflammatory signaling contributes to pulmonary damage. Our ongoing studies suggest that S. aureus directly activate na�ve CD4+ T cells through expression of multiple superantigens resulting in a hyperinflammatory response. Resident alveolar macrophages, through expression of cytokines such as IL-27 and co-inhibitory signals such as PD-L1, normally function to regulate T cell activation. In the experiments proposed we will establish how S. aureus induced necroptosis may limit the contribution of macrophage immunoregulatory molecules in T cell regulation and whether the macrophage-T cell interaction could be therapeutic target to improve the outcome of methicillin-resistant S. aureus (MRSA) pneumonia. This will be accomplished using wild type and knockout murine models of acute pneumonia, human PBMCs, alveolar macrophages and cell lines. Strategies to prevent T cell activation, by increasing macrophage numbers, blocking co-stimulatory proteins, or delivering exogenous co-inhibitory molecules will be evaluated for their efficacy in the setting of acute MRSA pneumonia. Given the limited efficacy of currently available antibiotics in the setting of MRSA infection, we postulate that enhancing normal immune clearance mechanisms could greatly benefit outcome.

描述（由申请人提供）：金黄色葡萄球菌是一种主要的人类病原体，与多种类型的感染相关，包括严重肺炎。金黄色葡萄球菌激活肺部中涉及气道上皮以及中性粒细胞、肺泡巨噬细胞的多种、通常是多余的促炎信号级联。、树突状细胞和招募的 T 细胞虽然中性粒细胞对于根除金黄色葡萄球菌至关重要，但过度的促炎信号传导。我们正在进行的研究表明，金黄色葡萄球菌通过表达多种超抗原，通过表达细胞因子（如 IL-27）和共抑制信号（如），直接激活幼稚 CD4+ T 细胞，从而导致肺泡巨噬细胞产生过度炎症反应。 PD-L1 通常具有调节 T 细胞激活的功能，在我们提出的实验中，我们将确定金黄色葡萄球菌诱导的坏死性凋亡如何限制巨噬细胞免疫调节分子在 T 细胞调节中的作用。巨噬细将评估通过增加巨噬细胞数量、阻断共刺激蛋白或递送外源共抑制分子来防止 T 细胞激活的策略在急性 MRSA 肺炎中的疗效。鉴于目前可用的抗生素在 MRSA 感染中的疗效有限，我们假设增强正常的免疫清除机制可以极大地改善结果。