Immunopathogenesis of cerebral malaria
Immunopathogenesis of cerebral malaria
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DOI：
10.1016/j.ijpara.2006.02.016
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发表时间：
2006-05-01
影响因子：
4
通讯作者：
Ball, Helen J.
中科院分区：
文献类型：
--
作者：
Hunt, Nicholas H.;Golenser, Jacob;Ball, Helen J.
疟疾是最重要的全球健康问题之一，可能影响世界三分之一以上的人口。脑型疟疾（CM）是恶性疟原虫感染的致命并发症，但其发病机制仍不完全清楚。在这篇综述中，我们讨论了一些主要的致病事件，已被描述在小鼠模型的疾病，并将它们与人类的条件。CM发病机制中的最早期事件之一似乎是血脑屏障对蛋白质的渗透性的轻度增加。最近的研究表明，CD 8（+）T细胞在介导微血管内皮损伤中的作用，这种损伤可导致细胞因子、疟疾抗原和其他潜在有害分子穿过血脑屏障进入脑实质。我们认为，这反过来又导致小胶质细胞的激活和星形胶质细胞的激活和凋亡。缺氧在脑型疟疾发病机制中的作用也进行了讨论，特别是局部减少脑中的氧消耗作为血管阻塞的结果，以甜菜碱驱动的葡萄糖代谢的变化，和细胞病变缺氧。干扰素-γ，一种已知在疟疾感染中产生的细胞因子，通过微血管内皮细胞诱导血红素酶吲哚胺2，3-双加氧酶（色氨酸代谢的犬尿氨酸途径中的第一种酶）的表达增加。吲哚胺2，3-双加氧酶表达增强导致一系列生物活性代谢物的产生增加，这些代谢物可能是组织保护性反应的一部分。对星形胶质细胞的损伤可能导致神经保护分子犬尿烯酸的产生减少，导致其相对于神经兴奋毒性分子喹啉酸的比例降低，这可能导致脑型疟疾的一些神经症状。最后，我们讨论了其他血红素酶，环氧合酶-2，诱导型一氧化氮合酶和血红素加氧酶-1的作用，作为潜在的保护宿主组织免受疟疾感染引起的细胞因子和白细胞介导的压力的影响的机制的组成部分。(c)2006年澳大利亚寄生虫学会由爱思唯尔有限公司出版。保留所有权利。
Malaria is one of the most important global health problems, potentially affecting more than one third of the world's population. Cerebral malaria (CM) is a deadly complication of Plasmodium falciparum infection, yet its pathogenesis remains incompletely understood. In this review, we discuss some of the principal pathogenic events that have been described in murine models of the disease and relate them to the human condition. One of the earliest events in CM pathogenesis appears to be a mild increase in the permeability to protein of the blood-brain barrier. Recent studies have shown a role for CD8(+)T cells in mediating damage to the microvascular endothelium and this damage can result in the leakage of cytokines, malaria antigens and other potentially harmful molecules across the blood-brain barrier into the cerebral parenchyma. We suggest that this, in turn, leads to the activation of microglia and the activation and apoptosis of astrocytes. The role of hypoxia in the pathogenesis of cerebral malaria is also discussed, with particular reference to the local reduction of oxygen consumption in the brain as a consequence of vascular obstruction, to cytokine-driven changes in glucose metabolism, and to cytopathic hypoxia. Interferon-gamma, a cytokine known to be produced in malaria infection, induces increased expression, by microvascular endothelial cells, of the haem enzyme indoleamine 2,3-dioxygenase, the first enzyme in the kynurenine pathway of tryptophan metabolism. Enhanced indoleamine 2,3-dioxygenase expression leads to increased production of a range of biologically active metabolites that may be part of a tissue protective response. Damage to astrocytes may result in reduced production of the neuroprotectant molecule kynurenic acid, leading to a decrease in its ratio relative to the neuroexcitotoxic molecule quinolinic acid, which might contribute to some of the neurological symptoms of cerebral malaria. Lastly, we discuss the role of other haem enzymes, cyclooxygenase-2, inducible nitric oxide synthase and haem oxygenase-1, as potentially being components of mechanisms that protect host tissue against the effects of cytokine- and leukocyte-mediated stress induced by malaria infection. (c) 2006 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.