Chlamydia Pneumoniae Antigens of Bilogogical Significance

具有双意义的肺炎衣原体抗原

• 批准号: 7792341
• 负责人: LEE ANN CAMPBELL
• 金额: $ 38.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/7792341
• 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; 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; Polysaccharides; Prevention; Protein Analysis; Proteins; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Role; Sinusitis; Small Interfering RNA; Specificity; Testing; Ubiquitin; Up-Regulation; base; in vitro testing; in vivo; inhibitor/antagonist; low density lipoprotein inhibitor; major outer membrane protein; mannose receptor; monocyte; mortality; mouse model; novel; obligate intracellular parasite; oxidized low density lipoprotein; pathogen; prevent; public health relevance; receptor; receptor expression; receptor mediated endocytosis; research study; respiratory; scavenger receptor; trafficking; ubiquitin ligase; uptake

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，引起5-10%的肺炎支气管炎和鼻窦炎。这种病原体还与动脉粥样硬化及其相关的临床表现，如冠心病，在美国，肺炎梭菌是导致发病和死亡的主要原因，在动脉粥样硬化病变中被发现，但在正常组织中很少发现。体外实验表明，肺炎梭菌在动脉粥样硬化中所起作用的生物学合理性已得到证实，该实验表明，肺炎梭菌可诱导致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，肺炎梭菌感染加速动脉粥样硬化病变的形成。关键的发病机制和发展策略，以防止感染是鉴定这种专性细胞内寄生虫是如何内化。我们已经证明衣原体聚糖（一种高甘露糖低聚糖）对传染性至关重要，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。我们也有初步结果表明，肺炎梭菌可能结合凝集素样氧化LDL清除率受体（LOX-1）。该受体的表达由ox-LDL诱导，导致ox-LDL摄取增加和促动脉粥样硬化因子的表达。已发现肺炎梭菌也能诱导相同的因子，但其机制尚不清楚。有待验证的新假设是，肺炎梭菌诱导LOX-1受体的表达，导致机体内吞和促动脉粥样硬化因子的表达，这有助于肺炎梭菌加速动脉粥样硬化，通过抑制LOX-1起作用的药物治疗可以预防肺炎梭菌加速动脉粥样硬化。总的来说，衣原体进入宿主细胞的机制仍然难以捉摸，可能涉及不止一种途径。我们的研究表明，衣原体可以通过MR或M6PR进入，两者都是通过网格蛋白介导的内吞作用内化的，这表明衣原体可以通过这一途径进入。使用网格蛋白和泛素内吞抑制剂，我们已经证明肺炎球菌的传染性可以被抑制。因此，我们将验证衣原体可能使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感染和再感染。这一建议旨在确定生物体如何附着并进入宿主细胞以建立感染。如果这种微生物与心血管疾病的病理有关，那么确定干预或预防的目标对公共卫生至关重要。