The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen–encoding var genes

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.在人体宿主内，恶性疟原虫（Plasmodium falciparum）会面临多种选择压力。罹患重症疟疾时，宿主内环境会发生剧烈变化，但疟原虫对该环境作出响应或被其选择的程度仍不明确。既往研究显示，引发重症疟疾的疟原虫会上调一类范围受限但定义模糊的恶性疟原虫红细胞膜蛋白1（PfEMP1）变异体（表面抗原）亚组的表达。PfEMP1是保护性免疫的核心靶标。本研究采用RNA测序（RNA sequencing, RNAseq）技术，对44株从巴布亚患者体内分离的疟原虫进行基因表达分析，这些疟原虫分别引发了重症疟疾和非复杂性疟疾。对19株与重症疟疾相关的疟原虫分离株的转录组分析显示，此类疟原虫的糖酵解水平下调且未激活代偿通路；染色质结构发生改变，且可能通过降低组蛋白甲基化水平调控转录；PfEMP1的表面表达量降低；多种伴侣蛋白的表达均出现下调。本次RNAseq分析还发现了疾病严重程度与PfEMP1转录本、结构域及较小序列片段之间的全新关联，并验证了此前所有已报道的、表达型PfEMP1序列与重症疟疾之间的关联。本研究结果可为重症疟疾疫苗靶标的筛选工作提供参考，同时也阐明了疟原虫在重症疟疾宿主环境中的适应机制或被选择的过程。