Chlamydia Pneumoniae Antigens of Bilogogical Significance

具有双意义的肺炎衣原体抗原

基本信息

批准号：
7522452
负责人：
LEE ANN CAMPBELL
金额：
$ 39万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7522452
关键词：
Adherence Affect Animal Model Antibodies Antigens Antisense RNA Arterial Fatty Streak Atherosclerosis Binding Biological Blood Vessels Bronchitis CCL2 gene Carbohydrates Cardiovascular Diseases Cell Adhesion Molecules Cells Chemical Structure Chlamydia Chlamydophila pneumoniae Clathrin Clinical Coronary heart disease Development Dominant-Negative Mutation Endocytosis Endosomes Endothelial Cells Funding Human IGF Type 2 Receptor Immunoblot Analysis Immunoprecipitation In Vitro Infection Infection prevention Intervention Lectin Lectin Receptors Ligand Binding Ligands Link Lung diseases Mannose Matrix Metalloproteinases Mediating Morbidity - disease rate Normal tissue morphology Oligosaccharides Organism Pathogenesis Pathology Pathway interactions Pilot Projects Pneumonia Polymerase Chain Reaction Polysaccharides Prevention Protein Analysis Proteins Public Health Reverse Transcriptase Polymerase Chain Reaction Role Sinusitis Small Interfering RNA Specificity Testing Ubiquitin Up-Regulation base in vivo inhibitor/antagonist low density lipoprotein inhibitor major outer membrane protein mannose receptor monocyte mortality mouse model novel obligate intracellular parasite oxidized LDL receptors oxidized low density lipoprotein pathogen prevent receptor receptor expression receptor mediated endocytosis research study respiratory scavenger receptor trafficking ubiquitin ligase uptake

项目摘要

DESCRIPTION (provided by applicant): Chlamydia pneumoniae is an etiological agent of human respiratory disease, causing 5-10% of pneumoniae bronchitis and sinusitis. This pathogen has also been associated with atheroscleroisis and its related clinical manifestations such as coronary heart disease, the leading cause of morbidity and mortality in the U.S. C. pneumoniae has been found in atherosclerotic lesions but rarely in normal tissues The biological plausibility of a role in atherosclerosis has been indicated by in vitro experiments demonstrating that C. pneumoniae induces the expression of proatherogenic factors and affects cellular pathways that to atherosclerosis. In hyperlipidemic animal models, C. pneumoniae infection accelerates atherosclerotic lesion formation. Key to pathogenesis and development of strategies to prevent infection is identification for how this obligate intracellular parasite is internalized. We have shown that the chlamydial glycan, a high mannose oligosaccharide, is critical for infectivity and that C. pneumoniae uses the mannose-6-phosphate receptor while C. trachomatis uses the mannose receptor for entry into the host. We also have preliminary results demonstrating that C. pneumoniae may bind to the lectin-like scavenger receptor for oxidized LDL (LOX-1). Expression of this receptor is induced by ox-LDL resulting in increased uptake of ox-LDL and expression of proatherogenic factors. C. pneumoniae has been found to induce the same factors, but the mechanism by which it does so is unknown. The novel hypotheses to be tested is that C. pneumoniae induces expression of the LOX-1 receptor resulting in endocytosis of the organism and in the expression of proatherogenic factors, which contribute to C. pneumoniae accelerated atherosclerosis and that treatment with agents that act through inhibition of LOX-1 will prevent C. pneumoniae accelerated atherosclerosis. Overall, the mechanisms by which chlamydiae enter the host cell have remained elusive and may involve more than one pathway. Our studies demonstrating that the chlamydiae spp. can use either the MR or M6PR for entry, both of which are internalized through clathrin mediated endocytosis, suggest that chlamydiae can enter through this pathway. Using inhibitors of clathrin and ubiqutin endocytosis, we have shown that the infectivity of C. pneumoniae could be inhibited. Thus, we will test the hypothesis that chlamydiae may use these pathways for entry into the host. PUBLIC HEALTH RELEVANCE: Chlamydia pneumoniae is a ubiquitous respiratory pathogen and everyone is infected and re-infected during his/her lifetime. This proposal seeks to identify how the organism attaches and enters into host cells to establish infection. If this organism contributes to the pathology of cardiovascular disease, identification of targets for intervention or prevention is of paramount importance to public health.

描述（申请人提供）：肺炎衣原体是人类呼吸道疾病的病原体，引起5-10%的肺炎、支气管炎和鼻窦炎。该病原体还与动脉粥样硬化及其相关临床表现（如冠心病）相关，冠心病是美国发病和死亡的主要原因。肺炎衣原体已在动脉粥样硬化病变中发现，但很少在正常组织中发现。在动脉粥样硬化中发挥作用的生物学合理性已得到证实。体外实验表明，肺炎衣原体诱导促动脉粥样硬化因子的表达并影响导致动脉粥样硬化的细胞途径。在高脂血症动物模型中，肺炎衣原体感染加速动脉粥样硬化病变的形成。发病机制和制定预防感染策略的关键是确定这种专性细胞内寄生虫如何内化。我们已经证明，衣原体聚糖（一种高甘露糖寡糖）对于感染性至关重要，肺炎衣原体使用甘露糖 6-磷酸受体，而沙眼衣原体使用甘露糖受体进入宿主。我们还有初步结果表明肺炎衣原体可能与氧化低密度脂蛋白 (LOX-1) 的凝集素样清道夫受体结合。该受体的表达由 ox-LDL 诱导，导致 ox-LDL 的摄取增加和促动脉粥样硬化因子的表达增加。已发现肺炎衣原体可诱导相同的因子，但其作用机制尚不清楚。待测试的新假设是肺炎衣原体诱导 LOX-1 受体的表达，导致生物体的内吞作用和促动脉粥样硬化因子的表达，这有助于肺炎衣原体加速动脉粥样硬化，并且通过抑制作用的药物进行治疗LOX-1可以预防肺炎衣原体加速动脉粥样硬化。总体而言，衣原体进入宿主细胞的机制仍然难以捉摸，并且可能涉及不止一种途径。我们的研究表明，衣原体属。可以使用 MR 或 M6PR 进入，两者均通过网格蛋白介导的内吞作用内化，表明衣原体可以通过此途径进入。使用网格蛋白和泛素内吞作用抑制剂，我们已经证明可以抑制肺炎衣原体的感染性。因此，我们将检验衣原体可能利用这些途径进入宿主的假设。公共卫生相关性：肺炎衣原体是一种普遍存在的呼吸道病原体，每个人在其一生中都会被感染和再次感染。该提案旨在确定生物体如何附着并进入宿主细胞以建立感染。如果这种生物体导致心血管疾病的病理学，那么确定干预或预防的目标对于公共卫生至关重要。