Pathogenesis of Cerebral Malaria: Recent Experimental Data and Possible Applications for Humans

Malaria still is a major public health problem, partly because the pathogenesis of its major complication, cerebral malaria, remains incompletely understood. Experimental models represent useful tools to better understand the mechanisms of this syndrome. Here, data generated by several models are reviewed both in vivo and in vitro; we propose that some pathogenic mechanisms, drawn from data obtained from experiments in a mouse model, may be instrumental in humans. In particular, tumor necrosis factor (TNF) receptor 2 is involved in this syndrome, implying that the transmembrane form of TNF may be more important than the soluble form of the cytokine. It has also been shown that in addition to differences in immune responsiveness between genetically resistant and susceptible mice, there are marked differences at the level of the target cell of the lesion, namely, the brain endothelial cell. In murine cerebral malaria, a paradoxical role of platelets has been proposed. Indeed, platelets appear to be pathogenic rather than protective in inflammatory conditions because they can potentiate the deleterious effects of TNF. More recently, it has been shown that interactions among platelets, leukocytes, and endothelial cells have phenotypic and functional consequences for the endothelial cells. A better understanding of these complex interactions leading to vascular injury will help improve the outcome of cerebral malaria.

疟疾仍是一项重大公共卫生难题，究其部分原因在于其主要并发症脑型疟疾（cerebral malaria）的发病机制仍未完全阐明。实验模型是深入解析该综合征发病机制的重要研究工具。本文综述了多个模型产生的体内（in vivo）与体外（in vitro）研究数据；我们提出，从小鼠模型实验数据中提炼的部分致病机制，或许在人类病例中同样发挥关键作用。尤为值得关注的是，该综合征的发生与肿瘤坏死因子（tumor necrosis factor, TNF）受体2密切相关，这提示TNF的跨膜形式或许比其可溶性细胞因子形式发挥更为关键的致病作用。研究还证实，除了遗传抗性小鼠与易感小鼠之间存在免疫应答差异外，病变靶细胞——即脑内皮细胞——层面也存在显著差异。在小鼠脑型疟疾模型中，血小板的作用呈现出矛盾性：在炎症状态下，血小板非但不具备保护作用，反而会加重病情，因为它们可增强TNF的有害效应。近期更有研究表明，血小板、白细胞与内皮细胞之间的相互作用会对内皮细胞产生表型与功能层面的影响。深入解析这些介导血管损伤的复杂相互作用，将有助于改善脑型疟疾的临床结局。