Activated Neutrophils Are Associated with Pediatric Cerebral Malaria Vasculopathy in Malawian Children
Activated Neutrophils Are Associated with Pediatric Cerebral Malaria Vasculopathy in Malawian Children
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DOI：
10.1128/mbio.01300-15
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发表时间：
2016-01-01
期刊：
影响因子：
6.4
通讯作者：
Daily, Johanna P.
中科院分区：
文献类型：
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作者：
Feintuch, Catherine Manix;Saidi, Alex;Daily, Johanna P.
大多数脑型疟疾（CM）患者维持脑微血管隔离恶性疟原虫感染的红细胞（irbc）。虽然许多幼儿感染恶性疟原虫，CM仍然是一种罕见的结果；因此，我们假设特定的宿主条件促进了iRBC的脑隔离。为了确定这些宿主因子，我们比较了患有iRBC脑隔离的马拉维儿童的外周全血转录组，被确定为疟疾视网膜病变阳性CM (Ret+CM)，与患有CM而没有脑隔离的儿童的转录组，被定义为疟疾视网膜病变阴性CM （Ret-CM）。Ret+CM与103个基因集通路上调相关，包括细胞因子、凝血和细胞外基质（ECM）通路（P < 0.01；假发现率[FDR] < 0.05）。中性粒细胞转录本是Ret+CM患者中最高上调的个体转录本。活化的中性粒细胞可以调节多种宿主过程，包括ECM、炎症和血小板生物学，从而潜在地促进寄生虫的隔离。因此，我们比较了Ret+CM和Ret-CM患者的血浆中性粒细胞蛋白和中性粒细胞趋化性。Ret+CM患者血浆中性粒细胞弹性酶、髓过氧化物酶和蛋白酶3水平升高，但不包括乳铁蛋白或脂钙蛋白，中性粒细胞趋化性受损，可能与血浆血红素增加有关。在CM脑微血管解剖样本中很少见到中性粒细胞，也没有发现中性粒细胞胞外陷阱，这表明假定的中性粒细胞对内皮细胞生物学的影响是由中性粒细胞可溶性因子引起的，而不是直接的中性粒细胞细胞组织效应。同时，Ret-CM患儿炎症水平较低，α -干扰素水平较高，toll样受体通路和其他宿主转录通路上调，这可能代表了不利于脑iRBC隔离的反应。2013年，全世界约有1.98亿疟疾病例，估计有584 000人死亡，其中大多数是撒哈拉以南非洲儿童。CM是恶性疟原虫感染的一种严重而罕见的形式，尽管进行了抗疟疾治疗，但仍与高死亡率和神经系统发病率相关。更好地了解CM的病理生理学将允许辅助治疗的发展，以改善临床结果。CM的一个标志是恶性疟原虫感染的红细胞（irbc）的脑微血管隔离，这在一些患者中导致血管病变。我们的数据提供了与CM相关的宿主途径的全局分析，并新确定了活化的中性粒细胞与脑iRBC隔离的关联。活化中性粒细胞的产物可以改变内皮细胞受体和凝血，促进iRBC粘附。未来的研究现在可以检查中性粒细胞在CM发病机制中的作用，以改善健康结果。
Most patients with cerebral malaria (CM) sustain cerebral microvascular sequestration of Plasmodium falciparum-infected red blood cells (iRBCs). Although many young children are infected with P. falciparum, CM remains a rare outcome; thus, we hypothesized that specific host conditions facilitate iRBC cerebral sequestration. To identify these host factors, we compared the peripheral whole-blood transcriptomes of Malawian children with iRBC cerebral sequestration, identified as malarial-retinopathy-positive CM (Ret+CM), to the transcriptomes of children with CM and no cerebral iRBC sequestration, defined as malarial-retinopathy-negative CM (Ret-CM). Ret+CM was associated with upregulation of 103 gene set pathways, including cytokine, blood coagulation, and extracellular matrix (ECM) pathways (P < 0.01; false-discovery rate [FDR] of < 0.05). Neutrophil transcripts were the most highly upregulated individual transcripts in Ret+CM patients. Activated neutrophils can modulate diverse host processes, including the ECM, inflammation, and platelet biology to potentially facilitate parasite sequestration. Therefore, we compared plasma neutrophil proteins and neutrophil chemotaxis between Ret+CM and Ret-CM patients. Plasma levels of human neutrophil elastase, myeloperoxidase, and proteinase 3, but not lactoferrin or lipocalin, were elevated in Ret+CM patients, and neutrophil chemotaxis was impaired, possibly related to increased plasma heme. Neutrophils were rarely seen in CM brain microvasculature autopsy samples, and no neutrophil extracellular traps were found, suggesting that a putative neutrophil effect on endothelial cell biology results from neutrophil soluble factors rather than direct neutrophil cellular tissue effects. Meanwhile, children with Ret-CM had lower levels of inflammation, higher levels of alpha interferon, and upregulation of Toll-like receptor pathways and other host transcriptional pathways, which may represent responses that do not favor cerebral iRBC sequestration.IMPORTANCE There were approximately 198 million cases of malaria worldwide in 2013, with an estimated 584,000 deaths occurring mostly in sub-Saharan African children. CM is a severe and rare form of Plasmodium falciparum infection and is associated with high rates of mortality and neurological morbidity, despite antimalarial treatment. A greater understanding of the pathophysiology of CM would allow the development of adjunctive therapies to improve clinical outcomes. A hallmark of CM is cerebral microvasculature sequestration of P. falciparum-infected red blood cells (iRBCs), which results in vasculopathy in some patients. Our data provide a global analysis of the host pathways associated with CM and newly identify an association of activated neutrophils with brain iRBC sequestration. Products of activated neutrophils could alter endothelial cell receptors and coagulation to facilitate iRBC adherence. Future studies can now examine the role of neutrophils in CM pathogenesis to improve health outcomes.