Wellcome Trust Centre for Human Genetics, Oxford, UK.
King Abdulla University of Science and Technology, Thuwal, Saudi Arabia.
Malar J. 2018 Sep 24;17(1):337. doi: 10.1186/s12936-018-2487-y.
Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection. A number of pathological findings have been correlated with pediatric CM including sequestration, platelet accumulation, petechial haemorrhage and retinopathy. However, the molecular mechanisms leading to death in CM are not yet fully understood.
A shotgun plasma proteomic study was conducted using samples form 52 Gambian children with CM admitted to hospital. Based on clinical outcome, children were assigned to two groups: reversible and fatal CM. Label-free liquid chromatography-tandem mass spectrometry was used to identify and compare plasma proteins that were differentially regulated in children who recovered from CM and those who died. Candidate biomarkers were validated using enzyme immunoassays.
The plasma proteomic signature of children with CM identified 266 proteins differentially regulated in children with fatal CM. Proteins from the coagulation cascade were consistently decreased in fatal CM, whereas the plasma proteomic signature associated with fatal CM underscored the importance of endothelial activation, tissue damage, inflammation, haemolysis and glucose metabolism. The concentration of circulating proteasomes or PSMB9 in plasma was not significantly different in fatal CM when compared with survivors. Plasma PSMB9 concentration was higher in patients who presented with seizures and was significantly correlated with the number of seizures observed in patients with CM during admission.
The results indicate that increased tissue damage and hypercoagulability may play an important role in fatal CM. The diagnostic value of this molecular signature to identify children at high risk of dying to optimize patient referral practices should be validated prospectively.
脑型疟疾（CM）是恶性疟原虫感染引起的严重神经并发症。已有多项病理学发现与儿科 CM 相关，包括疟原虫寄生、血小板聚集、瘀点性出血和视网膜病变。然而，导致 CM 死亡的分子机制尚未完全阐明。
对来自 52 名患有 CM 的冈比亚儿童的样本进行了无标记血浆蛋白质组学研究。根据临床结果，将儿童分为两组：可恢复性 CM 和致死性 CM。使用无标记液相色谱-串联质谱法比较和鉴定从 CM 中恢复的儿童和死亡儿童之间差异调节的血浆蛋白。使用酶联免疫吸附测定法验证候选生物标志物。
CM 儿童的血浆蛋白质组学特征确定了 266 种在致死性 CM 儿童中差异调节的蛋白质。凝血级联中的蛋白质在致死性 CM 中持续减少，而与致死性 CM 相关的血浆蛋白质组学特征强调了内皮激活、组织损伤、炎症、溶血和葡萄糖代谢的重要性。与幸存者相比，致死性 CM 患者血浆中的循环蛋白酶体或 PSMB9 浓度没有显著差异。出现癫痫发作的患者血浆 PSMB9 浓度较高，与 CM 患者住院期间观察到的癫痫发作次数显著相关。
结果表明，组织损伤增加和高凝状态可能在致死性 CM 中起重要作用。应前瞻性验证该分子特征对识别高死亡风险儿童的诊断价值，以优化患者转诊实践。
