Evolution of the Transmission-Blocking Vaccine Candidates Pvs28 and Pvs25 in Plasmodium vivax: Geographic Differentiation and Evidence of Positive Selection.
Evolution of the Transmission-Blocking Vaccine Candidates Pvs28 and Pvs25 in Plasmodium vivax: Geographic Differentiation and Evidence of Positive Selection.
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DOI：
10.1371/journal.pntd.0004786
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发表时间：
2016-06
影响因子：
3.8
通讯作者：
Escalante AA
中科院分区：
文献类型：
--
作者：
Chaurio RA;Pacheco MA;Cornejo OE;Durrego E;Stanley CE Jr;Castillo AI;Herrera S;Escalante AA
阻断传播（TB）疫苗被认为是控制和消除疟疾的重要工具。在所有抗间日疟原虫结核疫苗的抗原中，动动表面蛋白 Pvs28 和 Pvs25 是主要候选抗原。这些蛋白质可能起源于已知疟原虫物种辐射灵长类动物之前发生的基因复制事件。我们报告了对全球 pvs28 和 pvs25 等位基因样本的进化遗传分析。我们的结果表明，与裂殖子表面抗原 AMA-1 和 MSP-1 相比，这两个基因均表现出较低水平的遗传多态性；然而，这两种动动子抗原都可以与其他裂殖子抗原（例如 MSP-8 和 MSP-10）一样具有多态性。我们发现亚洲和美洲的寄生虫种群在地理上存在差异，具有相当水平的遗传多样性和仅在美洲发现的特定氨基酸替代。此外，观察到的变异主要积累在两种蛋白中间日疟原虫的 EGF2 和 EGF3 样结构域中。其他密切相关的非人类灵长类寄生虫（例如食蟹猴疟原虫）也具有这种模式，这表明它可能具有重要的功能。此外，通过一系列进化遗传分析进行的检查表明，观察到的模式与作用于 Pvs28 和 Pvs25 多态性的积极自然选择一致。遗传分化的地理模式和正选择的证据强烈表明，应在包括 Pvs25 和 Pvs28 在内的 TBV 发育过程中评估观察到的多态性的功能后果。间日疟原虫是非洲以外最流行的人类疟疾寄生虫。由于寄生虫的肝脏休眠阶段以及间日疟疾的其他生物学和流行病学特征，患者可能会复发，这一事实促进了该疾病在许多流行地区的持续存在。这些挑战推动了对新控制工具的探索，包括针对寄生虫性阶段的传播阻断 (TB) 疫苗。在这里，我们研究了两种主要结核疫苗抗原 Pvs25 和 Pvs28 的遗传多样性。我们表明，这些基因在世界范围内相对保守，但仍然具有多样性，但在基因之间分布不均匀。这些模式由密切相关的寄生虫物种中的相同蛋白质共享，表明它们的功能重要性。我们还发现亚洲和美洲发现的流行变种之间存在明显的地理差异。最后，进化遗传分析表明，观察到的两个基因的变异可以通过自然选择得以维持。因此，这些多态性可能赋予寄生虫适应性优势。这些结果表明疫苗开发商应考虑这些基因中发现的遗传变异及其地理分布。
Transmission-blocking (TB) vaccines are considered an important tool for malaria control and elimination. Among all the antigens characterized as TB vaccines against Plasmodium vivax, the ookinete surface proteins Pvs28 and Pvs25 are leading candidates. These proteins likely originated by a gene duplication event that took place before the radiation of the known Plasmodium species to primates. We report an evolutionary genetic analysis of a worldwide sample of pvs28 and pvs25 alleles. Our results show that both genes display low levels of genetic polymorphism when compared to the merozoite surface antigens AMA-1 and MSP-1; however, both ookinete antigens can be as polymorphic as other merozoite antigens such as MSP-8 and MSP-10. We found that parasite populations in Asia and the Americas are geographically differentiated with comparable levels of genetic diversity and specific amino acid replacements found only in the Americas. Furthermore, the observed variation was mainly accumulated in the EGF2- and EGF3-like domains for P. vivax in both proteins. This pattern was shared by other closely related non-human primate parasites such as Plasmodium cynomolgi, suggesting that it could be functionally important. In addition, examination with a suite of evolutionary genetic analyses indicated that the observed patterns are consistent with positive natural selection acting on Pvs28 and Pvs25 polymorphisms. The geographic pattern of genetic differentiation and the evidence for positive selection strongly suggest that the functional consequences of the observed polymorphism should be evaluated during development of TBVs that include Pvs25 and Pvs28. Plasmodium vivax is the most prevalent human malarial parasite outside Africa. The fact that patients can relapse due to the parasite dormant liver stages, among other biologic and epidemiologic characteristics of vivax malaria, facilitates the persistence of the disease in many endemic areas. These challenges have fueled the search for new control tools, including transmission blocking (TB) vaccines targeting the parasite sexual stages. Here we study the genetic diversity of two major TB vaccine antigens, Pvs25 and Pvs28. We show that these genes are relatively conserved worldwide but still harbor diversity that is not evenly distributed across the genes. These patterns are shared by the same proteins in closely related parasite species suggesting their functional importance. We also identify strong geographic differentiation between the circulating variants found in Asia and the Americas. Finally, evolutionary genetic analyses indicate that the observed variation in both genes could be maintained by natural selection. Thus, these polymorphisms may confer an adaptive advantage to the parasite. These results indicate that the genetic variation found in these genes and their geographic distribution should be considered by vaccine developers.