A Novel Domain Cassette Identifies Plasmodium falciparum PfEMP1 Proteins Binding ICAM-1 and Is a Target of Cross-Reactive, Adhesion-Inhibitory Antibodies
A Novel Domain Cassette Identifies Plasmodium falciparum PfEMP1 Proteins Binding ICAM-1 and Is a Target of Cross-Reactive, Adhesion-Inhibitory Antibodies
复制标题
DOI：
10.4049/jimmunol.1202578
复制
发表时间：
2013-01-01
影响因子：
4.4
通讯作者：
Jensen, Anja T. R.
中科院分区：
文献类型：
--
作者：
Bengtsson, Anja;Joergensen, Louise;Jensen, Anja T. R.
脑型恶性疟原虫疟疾的特征是受感染的红细胞（IE）粘附到脑微血管。这已经与表达IE粘附配体的恶性疟原虫红细胞膜蛋白1（PfEMP 1）家族的结构相关的A组亚群的寄生虫和对ICAM-1具有亲和力的IE相关联。然而，最近的证据对这两种关联产生了怀疑，降低了开发基于ICAM-1结合PfEMP 1的疫苗的可行性的希望。在这项研究中，我们报告了一个域盒（DC）的鉴定存在于A组变异基因从6个遗传上不同的恶性疟原虫寄生虫。我们称之为DC 4的表达盒中的三个结构域具有高水平的序列同一性，并在遗传学上聚集在一起。这些寄生虫感染的红细胞，并在体外选择表达DC 4粘附特异性ICAM-1。DC 4的ICAM-1结合能力定位于其Duffy结合样β 3结构域的C-末端三分之一。DC 4是广泛交叉反应性和粘附抑制性IgG抗体的靶点，在恶性疟原虫暴露儿童中，DC 4特异性和粘附抑制性IgG水平随年龄增加而增加。我们的研究挑战了早期的结论，即A组PfEMP 1蛋白不是ICAM-1特异性IE粘附的核心，并支持开发通过抑制脑IE隔离预防脑型疟疾的疫苗的可行性。免疫学杂志，2013，190：240-249。
Cerebral Plasmodium falciparum malaria is characterized by adhesion of infected erythrocytes (IEs) to the cerebral microvasculature. This has been linked to parasites expressing the structurally related group A subset of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family of IE adhesion ligands and to IEs with affinity for ICAM-1. However, recent evidence has cast doubt on both these associations, tempering hopes of the feasibility of developing a vaccine based on ICAM-1-binding PfEMP1. In this study, we report the identification of a domain cassette (DC) present in group A var genes from six genetically distinct P. falciparum parasites. The three domains in the cassette, which we call DC4, had a high level of sequence identity and cluster together phylogenetically. Erythrocytes infected by these parasites and selected in vitro for expression of DC4 adhered specifically to ICAM-1. The ICAM-1-binding capacity of DC4 was mapped to the C-terminal third of its Duffy-binding-like beta 3 domain. DC4 was the target of broadly cross-reactive and adhesion-inhibitory IgG Abs, and levels of DC4-specific and adhesion-inhibitory IgG increased with age among P. falciparum-exposed children. Our study challenges earlier conclusions that group A PfEMP1 proteins are not central to ICAM-1-specific IE adhesion and support the feasibility of developing a vaccine preventing cerebral malaria by inhibiting cerebral IE sequestration. The Journal of Immunology, 2013, 190: 240-249.