Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children
Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children
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DOI：
10.1073/pnas.1120455109
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发表时间：
2012-06-26
影响因子：
11.1
通讯作者：
Theander, Thor G.
中科院分区：
文献类型：
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作者：
Lavstsen, Thomas;Turner, Louise;Theander, Thor G.
恶性疟原虫感染的临床结果从无症状寄生虫病到与高死亡率相关的严重疟疾综合征不等。恶性疟原虫感染的毒力与感染红细胞表面表达的恶性疟原虫红细胞膜蛋白1 （PfEMP1）的类型有关，PfEMP1可以将这些红细胞固定在血管内壁上。尽管在2003年发现了与胎盘疟疾相关的var基因var2csa，但与儿童严重疟疾相关的var/PfEMP1变体的鉴定仍然难以捉摸。为了确定与严重疾病结局相关的var/PfEMP1变异，我们比较了88名患有严重疟疾的儿童和40名患有非复杂性疟疾的住院儿童寄生虫的var转录水平。转录本分析采用rt -定量PCR进行，使用一组42对引物扩增var亚型特异性位点，覆盖大多数var/PfEMP1亚型。此外，我们还鉴定了三名诊断为严重贫血和/或脑型疟疾的患者中最显著表达的var基因的近全长序列。联合分析表明，包括严重贫血和脑型疟疾在内的严重疟疾综合征与PfEMP1结构域编码var基因的高转录水平相关。A组var基因的转录水平，包括编码结构域盒13的基因，在患有严重综合征的患者中也明显高于那些没有并发症的疟疾患者。本研究明确了在儿童重症疟疾中表达的var/PfEMP1类型，从而为未来预防和治疗重症疟疾感染提供了独特的靶点。
The clinical outcome of Plasmodium falciparum infections ranges from asymptomatic parasitemia to severe malaria syndromes associated with high mortality. The virulence of P. falciparum infections is associated with the type of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of infected erythrocytes to anchor these to the vascular lining. Although var2csa, the var gene encoding the PfEMP1 associated with placental malaria, was discovered in 2003, the identification of the var/PfEMP1 variants associated with severe malaria in children has remained elusive. To identify var/PfEMP1 variants associated with severe disease outcome, we compared var transcript levels in parasites from 88 children with severe malaria and 40 children admitted to the hospital with uncomplicated malaria. Transcript analysis was performed by RT-quantitative PCR using a set of 42 primer pairs amplifying var subtype-specific loci covering most var/PfEMP1 subtypes. In addition, we characterized the near-full-length sequence of the most prominently expressed var genes in three patients diagnosed with severe anemia and/or cerebral malaria. The combined analysis showed that severe malaria syndromes, including severe anemia and cerebral malaria, are associated with high transcript levels of PfEMP1 domain cassette 8-encoding var genes. Transcript levels of group A var genes, including genes encoding domain cassette 13, were also significantly higher in patients with severe syndromes compared with those with uncomplicated malaria. This study specifies the var/PfEMP1 types expressed in severe malaria in children, and thereby provides unique targets for future efforts to prevent and treat severe malaria infections.