Combes Valéry, Coltel Nicolas, Faille Dorothée, Wassmer Samuel Crocodile, Grau Georges Emile
University of Sydney, Department of Pathology, Medical Foundation Building (K25), 92-94 Parramatta Road, Camperdown, NSW 2042, Australia.
Int J Parasitol. 2006 May 1;36(5):541-6. doi: 10.1016/j.ijpara.2006.02.005. Epub 2006 Mar 10.
Brain lesions of cerebral malaria (CM) are characterised by a sequestration of Plasmodium falciparum-parasitised red blood cells (PRBC), leucocytes and platelets within brain microvessels, by an excessive release of pro-inflammatory cytokines as well as by disruption of the blood-brain barrier (BBB). We evaluated the possibility that PRBC and platelets interact and induce functional alterations in brain endothelium. Using an in vitro model of endothelial lesion, we showed that platelets can act as bridges between PRBC and endothelial cells (EC) allowing the binding of PRBC to endothelium devoid of cytoadherence receptors. Furthermore, platelets potentiated the cytotoxicity of PRBC for brain EC by inducing an alteration of the integrity of their monolayer and increasing their apoptosis. These findings provide insights into the mechanisms by which platelets can be deleterious to the brain endothelium during CM. Another aspect of inflammatory and infectious diseases is that they often lead to activation of vascular and blood cells. Such activation results in an enhanced vesiculation, i.e. the release of circulating microparticles (MP). We thus explored plasma levels of endothelial MP in Malawian children with malaria. Plasma MP numbers were markedly increased on admission only in patients with severe malaria complicated with coma. Using the experimental mouse model of CM, we evaluated the pathogenic implications of MP using genetically deficient mice in which the capacity to vesiculate is impaired. Such mice, lacking the ABCA-1 gene, upon infection by Plasmodium berghei ANKA, showed complete resistance to CM. When purified from infected susceptible animals, MP were able to reduce normal plasma clotting time and to significantly enhance tumour necrosis factor release from naïve macrophages. Altogether these data provide a novel insight into the pathogenic mechanisms leading to the neurological syndrome. The finding that ABCA-1 gene deletion confers complete protection against cerebral pathology, linked to an impaired MP production, provides new potential targets for therapeutic amelioration of severe malaria.
脑型疟疾（CM）的脑部病变特征为，恶性疟原虫寄生的红细胞（PRBC）、白细胞和血小板在脑微血管内滞留，促炎细胞因子过度释放，以及血脑屏障（BBB）遭到破坏。我们评估了PRBC与血小板相互作用并诱导脑内皮细胞功能改变的可能性。利用内皮损伤的体外模型，我们发现血小板可充当PRBC与内皮细胞（EC）之间的桥梁，使PRBC能够与缺乏细胞黏附受体的内皮细胞结合。此外，血小板通过诱导脑EC单层完整性改变并增加其凋亡，增强了PRBC对脑EC的细胞毒性。这些发现为血小板在CM期间对脑内皮细胞产生有害作用的机制提供了见解。炎症和感染性疾病的另一个方面是，它们常常导致血管和血细胞激活。这种激活会导致囊泡化增强，即循环微粒（MP）的释放。因此，我们探究了马拉维疟疾患儿血浆中内皮MP的水平。仅在患有严重疟疾并伴有昏迷的患者入院时，血浆MP数量显著增加。利用CM的实验小鼠模型，我们使用囊泡化能力受损的基因缺陷小鼠评估了MP的致病影响。这种缺乏ABCA - 1基因的小鼠在感染伯氏疟原虫ANKA后，对CM表现出完全抗性。当从感染的易感动物中纯化MP时，MP能够缩短正常血浆凝血时间，并显著增强未接触过抗原的巨噬细胞释放肿瘤坏死因子。这些数据共同为导致神经综合征的致病机制提供了新的见解。ABCA - 1基因缺失赋予对脑部病变的完全保护这一发现，与MP产生受损有关，为严重疟疾的治疗改善提供了新的潜在靶点。
