Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS One. 2012;7(10):e46424. doi: 10.1371/journal.pone.0046424. Epub 2012 Oct 5.
BACKGROUND: Plasmodium falciparum elicits host inflammatory responses that cause the symptoms and severe manifestations of malaria. One proposed mechanism involves formation of immunostimulatory uric acid (UA) precipitates, which are released from sequestered schizonts into microvessels. Another involves hypoxanthine and xanthine, which accumulate in parasitized red blood cells (RBCs) and may be converted by plasma xanthine oxidase to UA at schizont rupture. These two forms of 'parasite-derived' UA stimulate immune cells to produce inflammatory cytokines in vitro. METHODS AND FINDINGS: We measured plasma levels of soluble UA and inflammatory cytokines and chemokines (IL-6, IL-10, sTNFRII, MCP-1, IL-8, TNFα, IP-10, IFNγ, GM-CSF, IL-1β) in 470 Malian children presenting with uncomplicated malaria (UM), non-cerebral severe malaria (NCSM) or cerebral malaria (CM). UA levels were elevated in children with NCSM (median 5.74 mg/dl, 1.21-fold increase, 95% CI 1.09-1.35, n = 23, p = 0.0007) and CM (median 5.69 mg/dl, 1.19-fold increase, 95% CI 0.97-1.41, n = 9, p = 0.0890) compared to those with UM (median 4.60 mg/dl, n = 438). In children with UM, parasite density and plasma creatinine levels correlated with UA levels. These UA levels correlated with the levels of seven cytokines [IL-6 (r = 0.259, p<0.00001), IL-10 (r = 0.242, p<0.00001), sTNFRII (r = 0.221, p<0.00001), MCP-1 (r = 0.220, p<0.00001), IL-8 (r = 0.147, p = 0.002), TNFα (r = 0.132, p = 0.006) and IP-10 (r = 0.120, p = 0.012)]. In 39 children, UA levels were 1.49-fold (95% CI 1.34-1.65; p<0.0001) higher during their malaria episode [geometric mean titer (GMT) 4.67 mg/dl] than when they were previously healthy and aparasitemic (GMT 3.14 mg/dl). CONCLUSIONS: Elevated UA levels may contribute to the pathogenesis of P. falciparum malaria by activating immune cells to produce inflammatory cytokines. While this study cannot identify the cause of elevated UA levels, their association with parasite density and creatinine levels suggest that parasite-derived UA and renal function may be involved. Defining pathogenic roles for parasite-derived UA precipitates, which we have not directly studied here, requires further investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00669084.
背景：疟原虫引起宿主炎症反应，导致疟疾的症状和严重表现。一种提出的机制涉及到免疫刺激性尿酸（UA）沉淀的形成，这些沉淀从被隔离的裂殖体释放到微血管中。另一种涉及到次黄嘌呤和黄嘌呤，它们在寄生的红细胞（RBC）中积累，并且可能在裂殖体破裂时被血浆黄嘌呤氧化酶转化为 UA。这两种形式的“寄生虫来源”UA 刺激免疫细胞在体外产生炎症细胞因子。
方法和发现：我们在 470 名患有单纯性疟疾（UM）、非脑严重疟疾（NCSM）或脑疟疾（CM）的马里儿童中测量了血浆可溶性 UA 和炎症细胞因子和趋化因子（IL-6、IL-10、sTNFRII、MCP-1、IL-8、TNFα、IP-10、IFNγ、GM-CSF、IL-1β）的水平。NCSM 患儿（中位数 5.74mg/dl，1.21 倍增加，95%CI 1.09-1.35，n=23，p=0.0007）和 CM 患儿（中位数 5.69mg/dl，1.19 倍增加，95%CI 0.97-1.41，n=9，p=0.0890）的 UA 水平升高与 UM 患儿（中位数 4.60mg/dl，n=438）相比。在 UM 患儿中，寄生虫密度和血浆肌酐水平与 UA 水平相关。这些 UA 水平与七种细胞因子的水平相关[IL-6（r=0.259，p<0.00001）、IL-10（r=0.242，p<0.00001）、sTNFRII（r=0.221，p<0.00001）、MCP-1（r=0.220，p<0.00001）、IL-8（r=0.147，p=0.002）、TNFα（r=0.132，p=0.006）和 IP-10（r=0.120，p=0.012）]。在 39 名儿童中，疟疾发作期间 UA 水平升高 1.49 倍（95%CI 1.34-1.65；p<0.0001）[几何平均滴度（GMT）4.67mg/dl]，高于他们之前健康且无寄生虫时的水平（GMT 3.14mg/dl）。
结论：UA 水平升高可能通过激活免疫细胞产生炎症细胞因子，从而导致疟原虫疟疾的发病机制。虽然本研究不能确定 UA 水平升高的原因，但它们与寄生虫密度和肌酐水平的相关性表明，寄生虫来源的 UA 和肾功能可能与此有关。定义我们这里没有直接研究的寄生虫来源 UA 沉淀的致病作用需要进一步研究。
试验注册：ClinicalTrials.gov NCT00669084。
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