Endothelial progenitor cells and malaria pathogenesis

描述(申请人提供)：疟疾是全球发病率和死亡率的主要原因。大多数死亡是由于感染恶性疟原虫(P.恶性疟原虫)造成的。脑型疟疾(CM)是这些患者死亡的主要原因。尽管恶性疟原虫具有很强的致病力，但人们对恶性疟原虫和脑型疟疾的病理生理学基础知之甚少。感染红细胞(IRBC)在微血管中的隔离是恶性疟原虫感染的主要病理表现。IRBC与内皮细胞的黏附是由其表面的旋钮介导的。这种相互作用导致内皮细胞损伤，病理和血浆von Willebrand因子水平(VWF)升高表明。受损微血管的修复可以通过局部内皮细胞的增殖或迁移，也可以通过骨髓来源的循环内皮祖细胞(EPC)的招募来实现。循环内皮祖细胞的减少与与微血管损伤相关的疾病的症状的发展有关，如心血管疾病。我们假设恶性疟原虫感染导致微血管损伤和修复之间的失衡。当循环内皮祖细胞减少，受损的内皮细胞无法替代时，就会发生脑型疟疾。这一提议的具体目的将检验宿主对微血管损伤的反应是导致CM发生的假设。将加纳南部不同严重程度(CM、无并发症疟疾和无症状寄生虫血症)的恶性疟原虫感染者与正常对照进行比较。目的1)确定循环内皮祖细胞水平是否与CM的发生有关。循环中的EPC水平将由FACS分析确定。据预测，CM患者循环内皮祖细胞水平较低。目的2)评价恶性疟原虫感染时骨髓对微血管损伤的反应。采用双抗体夹心法测定血浆SDF-1和VEGF水平。预计所有感染患者的SDF-1和VEGF水平都会升高。

DESCRIPTION (provided by applicant): Malaria is a major cause of morbidity and mortality worldwide. The majority of deaths are due to infections with Plasmodium falciparum (P. falciparum) parasites. Cerebral malaria (CM) is a major cause of death in these patients. Despite its virulence, the pathophysiologic basis of P. falciparum disease and cerebral malaria are poorly understood. Sequestration of infected red blood cells (iRBCs) in the microvasculature is a major pathologic finding in P. falciparum infections. iRBCs' adherence to endothelial cells is mediated by knobs on their surface. This interaction results in endothelial cell damage, as indicated by pathology and elevated plasma von Willebrand's factor levels (vWF). Repair of damaged microvasculature may occur either by the proliferation or migration of local endothelial cells or the recruitment of bone marrow derived circulating endothelial progenitor cells (EPCs). The reduction of circulating EPCs has been associated with the development of symptoms in diseases associated with microvascular damage, such as cardiovascular disease. We hypothesize that P. falciparum infection results in an imbalance between microvascular damage and repair. Cerebral malaria occurs when circulating EPCs are diminished and damaged endothelial cells cannot be replaced. The Specific Aims of this proposal will test the hypothesis that the host response to microvascular damage is responsible for the development of CM. P. falciparum infected patients in southern Ghana with different degrees of disease severity (CM, uncomplicated malaria and asymptomatic parasitemia) will be compared with normal controls. Aim 1) To determine if levels of circulating EPCs are associated with the development of CM. Circulating EPC levels will be determined by FACS analysis. Patients with CM are predicted to have low levels of circulating EPCs. Aim 2) To evaluate the bone marrow response to microvascular damage in P. falciparum infections. Plasma SDF-1 and VEGF levels will be determined by ELISA. All infected patients are predicted to have elevated SDF-1 and VEGF levels.