Cham Gerald K K, Turner Louise, Lusingu John, Vestergaard Lasse, Mmbando Bruno P, Kurtis Jonathan D, Jensen Anja T R, Salanti Ali, Lavstsen Thomas, Theander Thor G
Centre for Medical Parasitology at Department of International Health, Immunology, and Microbiology, University of Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark.
J Immunol. 2009 Sep 1;183(5):3356-63. doi: 10.4049/jimmunol.0901331. Epub 2009 Aug 12.
The binding of erythrocytes infected with mature blood stage parasites to the vascular bed is key to the pathogenesis of malignant malaria. The binding is mediated by members of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. PfEMP1s can be divided into groups, and it has previously been suggested that parasites expressing group A or B/A PfEMP1s are most pathogenic. To test the hypothesis that the first malaria infections in infants and young children are dominated by parasites expressing A and B/A PfEMP1s, we measured the plasma Ab level against 48 recombinant PfEMP1 domains of different groupings in 1342 individuals living in five African villages characterized by markedly different malaria transmission. We show that children progressively acquire a broader repertoire of anti-PfEMP1 Abs, but that the rate of expansion is governed by transmission intensity. However, independently of transmission intensity, Abs are first acquired to particular Duffy binding ligand-like domains belonging to group A or B/A PfEMP1s. The results support the view that anti-PfEMP1 Ab responses effectively structure the expenditure of the repertoire of PfEMP1 maintained by the parasite. Parasites expressing certain group A and B/A PfEMP1s are responded to first by individuals with limited previous exposure, and the resulting Abs reduce the fitness and pathogenicity of these parasites during subsequent infections. This allows parasites expressing less pathogenic PFEMP1s to dominate during later infections. The identification of PfEMP1 domains expressed by parasites causing disease in infants and young children is important for development of vaccines protecting against severe malaria.
成熟血液期疟原虫感染的红细胞与血管床的结合是恶性疟疾发病机制的关键。这种结合由恶性疟原虫红细胞膜蛋白1（PfEMP1）家族成员介导。PfEMP1可分为不同组，此前有研究表明，表达A组或B/A组PfEMP1的疟原虫致病性最强。为了验证婴幼儿初次疟疾感染以表达A组和B/A组PfEMP1的疟原虫为主导这一假说，我们检测了生活在五个疟疾传播情况明显不同的非洲村庄的1342名个体针对48个不同分组的重组PfEMP1结构域的血浆抗体水平。我们发现，儿童逐渐获得更广泛的抗PfEMP1抗体谱，但抗体谱的扩展速度受传播强度的控制。然而，无论传播强度如何，个体首先获得的是针对属于A组或B/A组PfEMP1的特定达菲结合配体样结构域的抗体。这些结果支持以下观点：抗PfEMP1抗体反应有效地构建了疟原虫维持的PfEMP1抗体库的消耗模式。表达某些A组和B/A组PfEMP1的疟原虫首先会被既往接触有限的个体所识别，产生的抗体在后续感染中会降低这些疟原虫的适应性和致病性。这使得表达致病性较低的PFEMP1的疟原虫在后续感染中占主导地位。鉴定导致婴幼儿发病的疟原虫所表达的PfEMP1结构域，对于开发预防重症疟疾的疫苗具有重要意义。
