The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen-encoding var genes.
The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen-encoding var genes.
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DOI：
10.1371/journal.pbio.2004328
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发表时间：
2018-03
期刊：
影响因子：
9.8
通讯作者：
Duffy MF
中科院分区：
文献类型：
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作者：
Tonkin-Hill GQ;Trianty L;Noviyanti R;Nguyen HHT;Sebayang BF;Lampah DA;Marfurt J;Cobbold SA;Rambhatla JS;McConville MJ;Rogerson SJ;Brown GV;Day KP;Price RN;Anstey NM;Papenfuss AT;Duffy MF
在人类宿主体内，恶性疟原虫面临多重选择压力。在严重的疟疾中，宿主环境发生了巨大的变化，但寄生虫对这种环境的反应或被这种环境选择的程度仍不清楚。从以前的研究来看，引起严重疟疾的寄生虫似乎增加了PfEMP1变体中一个有限但定义不明确的子集的表达，即表面抗原。pfemp1是保护性免疫的主要靶点。在这里，我们使用RNA测序（RNAseq）分析了导致巴布亚患者严重和简单疟疾的44种寄生虫分离株的基因表达。与严重疟疾相关的19株寄生虫的转录组表明，这些寄生虫在没有激活代偿通路的情况下糖酵解减少；染色质结构改变和可能通过组蛋白甲基化降低的转录调控；PfEMP1表面表达减少；下调多种伴侣蛋白的表达。我们的RNAseq还发现了疾病严重程度与PfEMP1转录本、结构域和较小序列段之间的新关联，并证实了所有先前报道的表达的PfEMP1序列与严重疾病之间的关联。这些发现将为确定严重疟疾疫苗靶点的工作提供信息，并且还表明寄生虫如何适应或被严重疟疾的宿主环境所选择。恶性疟原虫是导致人类疟疾的寄生虫，它的感染可导致严重的疾病，可能是致命的，也可能是一种可以由宿主免疫系统解决的简单疾病。然而，引起严重疾病的寄生虫与引起非复杂疾病的寄生虫是否不同尚不清楚。一些证据表明，引起严重疾病的寄生虫可能表达一组有限的恶性疟原虫红细胞膜蛋白1 （PfEMP1）蛋白。PfEMP1蛋白在被感染的红细胞表面表达并引发保护性免疫。我们比较了导致严重和简单疟疾的寄生虫的转录组，以确定这些寄生虫是否在它们表达的基因上有所不同。我们发现引起严重疟疾的寄生虫改变了参与基础代谢、核过程和PfEMP1表面表达的基因的表达。引起严重疟疾的寄生虫上调了一组PfEMP1蛋白的表达。其中一些pfemp1先前与严重疟疾有关，这为我们的数据提供了支持。在严重疟疾和表达的PfEMP1序列之间发现的多重关联是新的。这些新的严重疾病相关的PfEMP1序列可能有助于为设计针对严重疟疾的疫苗提供信息。
Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to—or is selected by—this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to—or are selected by—the host environment in severe malaria. Infection by Plasmodium falciparum—the parasite responsible for malaria in humans—can result in a severe disease that can be fatal or in an uncomplicated disease that can be resolved by the host immune system. However, whether the parasites causing severe disease differ from those causing uncomplicated disease is unknown. Several strands of evidence have suggested that parasites causing severe disease may express a restricted set of the Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) proteins. PfEMP1 proteins are expressed on the surface of the infected red blood cells and elicit protective immunity. We compared the transcriptomes of parasites causing severe and uncomplicated malaria to determine whether these parasites differed in the genes they expressed. We found that the parasites causing severe malaria had altered expression of genes involved in basic metabolism, nuclear processes, and surface expression of PfEMP1. The parasites causing severe malaria had up-regulated expression of a set of PfEMP1 proteins. Some of these PfEMP1s had been previously implicated in severe malaria, lending support to our data. Multiple associations identified between severe malaria and expressed PfEMP1 sequences were novel. These novel, severe disease–associated PfEMP1 sequences could be useful for informing design of vaccines targeting severe malaria disease.
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