Siau Anthony, Toure Fousseyni S, Ouwe-Missi-Oukem-Boyer Odile, Ciceron Liliane, Mahmoudi Nassira, Vaquero Catherine, Froissard Patrick, Bisvigou Ulrick, Bisser Sylvie, Coppee Jean-Yves, Bischoff Emmanuel, David Peter H, Mazier Dominique
Institut National de la Sante et de la Recherche Medicale U511, Paris 75013, France.
J Infect Dis. 2007 Dec 1;196(11):1603-12. doi: 10.1086/522012. Epub 2007 Oct 25.
Severe malaria and one of its most important pathogenic processes, cerebral malaria, involves the sequestration of parasitized red blood cells (pRBCs) in brain postcapillary venules. Although the pathogenic mechanisms underlying malaria remain poorly characterized, it has been established that adhesion of pRBCs to endothelial cells (ECs) can result in cell apoptosis, which in turn may lead to disruption of the blood-brain barrier. The nature of the parasite molecules involved in the pathogenesis of severe malaria remains elusive.
Whole-transcriptome profiling of nonapoptogenic versus apoptogenic parasite field isolates obtained from Gabonese children was performed with pan-genomic Plasmodium falciparum DNA microarrays; radiolabeled instead of fluorescent cDNAs were used to improve the sensitivity of signal detection.
Our methods allowed the identification of 59 genes putatively associated with the induction of EC apoptosis. Silencing of Plasmodium gene expression with specific double-stranded RNA was performed on 8 selected genes; 5 of these, named "Plasmodium apoptosis-linked pathogenicity factors" (PALPFs), were found to be linked to parasite apoptogenicity. Of these genes, 2 might act via parasite cytoadherence.
This is the first attempt to identify genes involved in parasite pathogenic mechanisms against human ECs. The finding of PALPFs illuminates perspectives for novel therapeutic strategies against cerebral complications of malaria.
重症疟疾及其最重要的致病过程之一——脑型疟疾，涉及寄生红细胞（pRBCs）在脑毛细血管后微静脉中的滞留。尽管疟疾的致病机制仍未完全明确，但已证实pRBCs与内皮细胞（ECs）的黏附可导致细胞凋亡，进而可能导致血脑屏障的破坏。参与重症疟疾发病机制的寄生虫分子的性质仍不清楚。
使用泛基因组恶性疟原虫DNA微阵列对从加蓬儿童获得的非凋亡性与凋亡性寄生虫野外分离株进行全转录组分析；使用放射性标记而非荧光cDNA来提高信号检测的灵敏度。
我们的方法鉴定出59个可能与诱导EC凋亡相关的基因。对8个选定基因进行了用特异性双链RNA沉默疟原虫基因表达的实验；其中5个基因，命名为“疟原虫凋亡相关致病因子”（PALPFs），被发现与寄生虫的凋亡性有关。在这些基因中，有2个可能通过寄生虫细胞黏附起作用。
这是首次尝试鉴定参与寄生虫针对人类ECs致病机制的基因。PALPFs的发现为针对疟疾脑部并发症的新型治疗策略提供了思路。
