Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria
Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria
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DOI：
10.2353/ajpath.2007.070630
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发表时间：
2007-12-01
影响因子：
6
通讯作者：
Liles, W. Conrad
中科院分区：
文献类型：
--
作者：
Lovegrove, Fiona E.;Gharib, Sina A.;Liles, W. Conrad
受寄生虫隔离和宿主免疫系统激活影响的特定局部脑反应与脑型疟疾的发展有关。本研究通过比较感染伯氏疟原虫ANKA的遗传抗性和易感近交系小鼠品系，评估了实验性脑型疟疾过程中全脑转录反应。计算方法被用来识别基因表达的差异模式。总体而言，表现出最转录活性的基因在脑型疟疾特征性症状发作前1至2天在易感小鼠中差异表达。大多数差异表达基因与免疫相关的基因本体分类有关。进一步分析以确定相互作用网络并检查一组已确定基因内的转录调节模式，表明干扰素调节过程和细胞凋亡在脑型疟疾发病机制中发挥着核心作用。这些基因和途径的生物学相关性通过定量RT-PCR和脑细胞凋亡的组织病理学检查来证实。应用计算生物学工具系统地研究脑型疟疾的疾病进展，可以确定其发病过程中激活的重要转录程序，并可能作为一种方法学途径来确定新的治疗干预靶点。
Specific local brain responses, influenced by parasite sequestration and host immune system activation, have been implicated in the development of cerebral malaria. This study assessed whole-brain transcriptional responses over the course of experimental cerebral malaria by comparing genetically resistant and susceptible inbred mouse strains infected with Plasmodium berghei ANKA. Computational methods were used to identify differential patterns of gene expression. Overall, genes that showed the most transcriptional activity were differentially expressed in susceptible mice 1 to 2 days before the onset of characteristic symptoms of cerebral malaria. Most of the differentially expressed genes identified were associated with immune-related gene ontology categories. Further analysis to identify interaction networks and to examine patterns of transcriptional regulation within the set of identified genes implicated a central role for both interferon-regulated processes and apoptosis in the pathogenesis of cerebral malaria. Biological relevance of these genes and pathways was confirmed using quantitative RT-PCR and histopathological examination of the brain for apoptosis. The application of computational biology tools to examine systematically the disease progression in cerebral malaria can identify important transcriptional programs activated during its pathogenesis and may serve as a methodological approach to identify novel targets for therapeutic intervention.