Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
PLoS One. 2013;8(1):e54481. doi: 10.1371/journal.pone.0054481. Epub 2013 Jan 22.
Inflammatory cytokinemia and systemic activation of the microvascular endothelium are central to the pathogenesis of Plasmodium falciparum malaria. Recently, 'parasite-derived' uric acid (UA) was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria.
METHODOLOGY/PRINCIPAL FINDINGS: We measured levels of UA and soluble forms of intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), E-selectin (sE-Selectin), thrombomodulin (sTM), tissue factor (sTF) and vascular endothelial growth factor (VEGF) in the plasma of Malian children aged 0.5-17 years with uncomplicated malaria (UM, n = 487) and non-cerebral severe malaria (NCSM, n = 68). In 69 of these children, we measured these same factors once when they experienced a malaria episode and twice when they were healthy (i.e., before and after the malaria transmission season). We found that levels of UA, sICAM-1, sVCAM-1, sE-Selectin and sTM increase during a malaria episode and return to basal levels at the end of the transmission season (p<0.0001). Plasma levels of UA and these four endothelial biomarkers correlate with parasite density and disease severity. In children with UM, UA levels correlate with parasite density (r = 0.092, p = 0.043), sICAM-1 (r = 0.255, p<0.0001) and sTM (r = 0.175, p = 0.0001) levels. After adjusting for parasite density, UA levels predict sTM levels.
CONCLUSIONS/SIGNIFICANCE: Elevated UA levels may contribute to malaria pathogenesis by damaging endothelium and promoting a procoagulant state. The correlation between UA levels and parasite densities suggests that parasitized erythrocytes are one possible source of excess UA. UA-induced shedding of endothelial TM may represent a novel mechanism of malaria pathogenesis, in which activated thrombin induces fibrin deposition and platelet aggregation in microvessels. This protocol is registered at clinicaltrials.gov (NCT00669084).
疟原虫引起的细胞因子血症和全身微血管内皮细胞的激活是恶性疟原虫病发病机制的核心。最近，研究表明“寄生虫来源”的尿酸（UA）可在体外激活人类免疫细胞，马里疟疾患儿的血浆 UA 水平与炎症细胞因子水平和疾病严重程度相关。由于 UA 与非疟疾疾病中的内皮炎症有关，我们假设升高的 UA 水平可能导致恶性疟原虫病的内皮病理学改变。
方法/主要发现：我们测量了 487 例无并发症疟疾（UM）和 68 例非脑严重疟疾（NCSM）的马里儿童 0.5-17 岁时的 UA 水平和可溶性细胞间黏附分子-1（sICAM-1）、血管细胞黏附分子-1（sVCAM-1）、E-选择素（sE-Selectin）、血栓调节蛋白（sTM）、组织因子（sTF）和血管内皮生长因子（VEGF）的血浆水平。在其中 69 名儿童中，我们在疟疾发作时、健康时（即疟疾传播季节前后）各测量了一次这些相同的因素。我们发现，UA、sICAM-1、sVCAM-1、sE-Selectin 和 sTM 的水平在疟疾发作期间升高，并在传播季节结束时恢复到基础水平（p<0.0001）。UA 和这四种内皮生物标志物的血浆水平与寄生虫密度和疾病严重程度相关。在 UM 患儿中，UA 水平与寄生虫密度（r = 0.092，p = 0.043）、sICAM-1（r = 0.255，p<0.0001）和 sTM（r = 0.175，p = 0.0001）水平相关。在调整寄生虫密度后，UA 水平可预测 sTM 水平。
结论/意义：升高的 UA 水平可能通过损伤内皮细胞和促进促凝状态来促进疟疾的发病机制。UA 水平与寄生虫密度之间的相关性表明，寄生红细胞可能是 UA 过量的一个可能来源。UA 诱导的内皮 TM 脱落可能代表一种新的疟疾发病机制，其中激活的凝血酶在微血管中诱导纤维蛋白沉积和血小板聚集。该方案在 clinicaltrials.gov 注册（NCT00669084）。
