Chlamydia Pneumoniae Antigens of Bilogogical Significance

描述(申请人提供)：肺炎衣原体是人类呼吸道疾病的病原体，可引起5-10%的肺炎支气管炎和鼻窦炎。这种病原体也与动脉粥样硬化及其相关的临床表现有关，如冠心病，美国肺炎衣原体致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，肺炎衣原体在动脉粥样硬化中发挥作用的生物学可能性已被证明，它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通路。在高脂血症动物模型中，肺炎衣原体感染会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是如何内化的。我们已经证明，衣原体多糖是一种高甘露糖低聚糖，对感染性至关重要，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。我们也有初步的结果表明肺炎链球菌可能与氧化低密度脂蛋白的凝集素样清道夫受体(LOX-1)结合。这种受体的表达是由氧化低密度脂蛋白诱导的，从而增加了氧化低密度脂蛋白的摄取和促动脉粥样硬化因子的表达。肺炎衣原体已被发现可诱发相同的因子，但其作用机制尚不清楚。有待检验的新假设是肺炎衣原体诱导LOX-1受体的表达，导致机体内吞作用，并诱导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，而通过抑制LOX-1作用的药物治疗将防止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，可能涉及多种途径。研究表明，衣原体属(Chlamydiae spp.)可以利用MR或M6PR进入，两者都是通过网状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。使用笼状蛋白和泛素内吞作用的抑制剂，我们已经证明肺炎链球菌的感染性可以被抑制。因此，我们将检验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，每个人都会在有生之年受到感染和再次感染。这项建议寻求确定有机体如何附着并进入宿主细胞以建立感染。如果这种微生物对心血管疾病的病理有贡献，那么确定干预或预防的目标对公共卫生至关重要。

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.