Trimnell Adama R, Kraemer Susan M, Mukherjee Sandeep, Phippard David J, Janes Joel H, Flamoe Eric, Su Xin-zhuan, Awadalla Philip, Smith Joseph D
Seattle Biomedical Research Institute, Seattle, WA, USA.
Mol Biochem Parasitol. 2006 Aug;148(2):169-80. doi: 10.1016/j.molbiopara.2006.03.012. Epub 2006 Apr 18.
In Plasmodium falciparum, var genes encode adhesive proteins that are transported to the surface of infected erythrocytes and act as major virulence determinants for infected erythrocyte binding and immune evasion. Var genes are highly diverse and can be classified into five major groups (UpsA, B, C, D, and E). Previous serological studies have suggested that the UpsA var group may contain common antigenic types that have important roles in severe childhood malaria. Here, our analysis found that UpsA vars are highly diverse between 22 world-wide parasite isolates, although they could be grouped into two broad clusters that may be separately recombining. By comparison, orthologs of the UpsA-linked Type 3 var and UpsE-linked var2csa were detected in nearly all parasite isolates, and a var2csa ortholog was also present in a chimpanzee malaria P. reichenowi that diverged from P. falciparum approximately 5-7 million years ago. Although the specific function of Type 3 var genes is unknown, var2csa is a leading candidate for a pregnancy associated malaria vaccine. Compared to typical var genes, var2csa is unusually conserved but still had only 54-94% amino acid identity in extracellular binding regions. However, var2csa alleles have extensive gene mosaicism within polymorphic blocks that are shared between world-wide parasite isolates and recognizable in P. rechenowi suggesting a high rate of self-self recombination and an ancient and globally-related pool of var2csa polymorphism. These studies aid our understanding of the evolutionary mechanisms that shape var diversity and will be important to the development of vaccines against pregnancy associated malaria and severe malaria.
在恶性疟原虫中，var基因编码黏附蛋白，这些蛋白被转运到被感染红细胞的表面，是被感染红细胞结合和免疫逃避的主要毒力决定因素。var基因高度多样化，可分为五个主要组（UpsA、B、C、D和E）。先前的血清学研究表明，UpsA var组可能包含在儿童重症疟疾中起重要作用的常见抗原类型。在这里，我们的分析发现，尽管22个全球寄生虫分离株中的UpsA vars可分为两个可能分别重组的宽泛簇，但它们之间高度多样化。相比之下，几乎在所有寄生虫分离株中都检测到了与UpsA相关的3型var和与UpsE相关的var2csa的直系同源物，并且在大约500 - 700万年前与恶性疟原虫分化的黑猩猩疟疾赖氏疟原虫中也存在var2csa直系同源物。虽然3型var基因的具体功能尚不清楚，但var2csa是妊娠相关疟疾疫苗的主要候选物。与典型的var基因相比，var2csa异常保守，但在细胞外结合区域的氨基酸同一性仍仅为54 - 94%。然而，var2csa等位基因在多态性区域内具有广泛的基因镶嵌性，这些区域在全球寄生虫分离株之间共享，并且在赖氏疟原虫中也可识别，这表明var2csa多态性存在高度的自我重组率以及古老且与全球相关的库。这些研究有助于我们理解塑造var多样性的进化机制，对于开发针对妊娠相关疟疾和重症疟疾的疫苗将具有重要意义。
