Evaluation of the genetic diversity of domain II of Plasmodium vivax Apical Membrane Antigen 1 (PvAMA-1) and the ensuing strain-specific immune responses in patients from Sri Lanka
Evaluation of the genetic diversity of domain II of Plasmodium vivax Apical Membrane Antigen 1 (PvAMA-1) and the ensuing strain-specific immune responses in patients from Sri Lanka
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DOI：
10.1016/j.vaccine.2011.07.029
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发表时间：
2011-10-06
期刊：
影响因子：
5.5
通讯作者：
Udagama, Preethi V.
中科院分区：
文献类型：
--
作者：
Dias, Sajani;Somarathna, Maheshika;Udagama, Preethi V.
疟疾寄生虫表现出的抗原多态性是一种逃避宿主免疫系统的扭曲模式。间日疟原虫顶膜抗原 1 (Pvama-1DII) 结构域 II 的普遍遗传多样性在来自斯里兰卡的 64 个单克隆间日疟原虫分离株中进行了表征，该国不稳定的疟疾盛行且强度较低。在斯里兰卡，Pvama-1DII 基因显示出微弱的减数分裂重组，并包含单核苷酸多态性 (SNP)。 11 个氨基酸 (a.a.) 变体位置定义为 21 个 a.a.单倍型有 9 种是该岛独有的，其中主要单倍型 H1 与参考萨尔瓦多 I 株相同。另外 376 个全球分散的分离株定义为 38 个氨基酸。单倍型（H22-H59），分别有 4 个和 26 个印度和泰国独有的单倍型。系统发育树显示没有聚类，其中大多数分离株具有最近的共同起源。在 PvAMA-1DII B 和 T 细胞表位中检测到的多态性证明了寄生虫利用的免疫逃避机制。大多数斯里兰卡患者对构象和线性 B 细胞表位产生抗体反应。通过排列 a.a. 来评估由于广泛的抗原多态性而产生的菌株特异性免疫。 PvAMA-1DII 序列与通过内部建立的针对 7 个 PvAMA-1DII 重叠合成肽 P01-P07 的间接 ELISA 测定的同源总 (IgM + IgG) 抗体反应。而抗体对含有多态性 a.a. 间日疟原虫临床分离株的 P01-P03、P06、P07 产生反应。 Sal I 的单倍型明显具有菌株超越性（交叉反应性），具有与 Sal I 菌株相同的分离株的个体观察到针对 7 种 PvAMA-1DII Sal-I 合成肽的不同抗体流行率，其中针对 P04 检测到的抗体流行率最高。 Sal I 菌株的 PvAMA-1DII 的位置 302-324（包括由 PfAMA-1 的侵袭抑制 4G2 单克隆抗体识别的表位）在所有 440 个受检查的局部和整体间日疟原虫分离株中高度保守。 P04 的高免疫原性增强了该区域的功能作用，并且可能指向一种可能的“保护性”抗 P04 抗体反应，引发从 IgM 到 IgG 的同种型转换，并且仅在流行居民中增加了对疟疾的接触。因此，PvAMA-1 结构域 II 环的保守性和看似“保护性”的性质使其成为斯里兰卡针对间日疟原虫无性红细胞阶段的鸡尾酒疫苗的假定竞争者。 (C) 2011 Elsevier Ltd. 保留所有权利。
Antigenic polymorphism displayed by malaria parasites is a skewed schema to escape the host immune system. The prevailing genetic diversity at domain II of the Plasmodium vivax Apical Membrane Antigen-1 (Pvama-1DII) was characterized in 64 single clone P. vivax isolates from Sri Lanka, where unstable malaria prevails with low intensity.In Sri Lanka, the Pvama-1DII gene showed meager meiotic recombination with the enclosure of single nucleotide polymorphisms (SNPs). Eleven amino acid (a.a.) variant positions defined 21 a.a. haplotypes with 9 unique to the island, where the predominant haplotype, H1, was identical to the reference Salvador I strain. A further 376 globally dispersed isolates defined 38 a.a. haplotypes (H22-H59), with 4 and 26 haplotypes exclusive to India and Thailand, respectively. The phylogenetic tree revealed no clustering, where most isolates had a very recent common origin.The polymorphism detected in PvAMA-1DII B and T cell epitopes evidenced an immune evasion mechanism exploited by the parasite. Majority of Sri Lankan patients developed antibody responses to both conformational and linear B cell epitopes.The ensuing strain-specific immunity due to extensive antigenic polymorphism was evaluated by aligning a.a. sequences of PvAMA-1DII with the homologous total (IgM + IgG) antibody responses assayed by in-house established indirect ELISAs against 7 PvAMA-1DII overlapping synthetic peptides, P01-P07. While the antibody responses to P01-P03, P06, P07 harbouring P. vivax clinical isolates with polymorphic a.a. haplotype to Sal I was clearly strain-transcending (cross-reactive), individuals with isolates identical to the Sal I strain observed varying antibody prevalence against the seven PvAMA-1DII Sal-I synthetic peptides, with the highest prevalence detected against P04.Synthetic peptide P04, spanning a.a. positions 302-324 of the PvAMA-1DII of the Sal I strain that included the epitope recognized by the invasion inhibitory 4G2 monoclonal antibody of PfAMA-1, was highly conserved in all 440 local and global P. vivax isolates examined. A functional role for this region is reinforced by the highly immunogenic nature of P04, and could point towards a presumably "protective" anti-P04 antibody response that elicited an isotype switch from IgM to IgG, with increasing exposure to malaria exclusively in endemic residents. Thus the conserved and seemingly "protective" nature of the domain II loop of PvAMA-1 makes it a putative contender to be included in a cocktail vaccine against P. vivax asexual erythrocytic stages in Sri Lanka. (C) 2011 Elsevier Ltd. All rights reserved.