Laboratory of Malariology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Vaccine. 2013 Feb 18;31(9):1334-9. doi: 10.1016/j.vaccine.2012.12.039. Epub 2013 Jan 4.
Populations of Plasmodium falciparum, the most virulent human malaria parasite, are diverse owing to wide levels of transmission and endemicity of infection. Genetic diversity of P. falciparum antigens, within and between parasite populations, remains a confounding factor in malaria pathogenesis as well as clinical trials of vaccine candidates. Variation of target antigens in parasite populations may arise from immune pressure depending on the levels of acquired immunity. Alternatively, similar to our study in housekeeping genes [Tanabe et al. Curr Biol 2010;70:1-7], within-population genetic diversity of vaccine candidate antigens may also be determined by geographical distance from a postulated origin in Central sub-Saharan Africa. To address this question, we obtained full-length sequences of P. falciparum genes, apical membrane antigen 1 (ama1) (n=459), circumsporozoite protein (csp) (n=472) and merozoite surface protein 1 (msp1) (n=389) from seven geographically diverse parasite populations in Africa, Southeast Asia and Oceania; and, together with previously determined sequences (n=13 and 15 for csp and msp1, respectively) analyzed within-population single nucleotide polymorphism (SNP) diversity. The three antigen genes showed SNP diversity that supports a model of isolation-by-distance. The standardized number of polymorphic sites per site, expressed as θ(S), indicates that 77-83% can be attributed by geographic distance from the African origin, suggesting that geographic distance plays a significant role in variation in target vaccine candidate antigens. Furthermore, we observed that a large proportion of SNPs in the antigen genes were shared between African and non-African parasite populations, demonstrating long term persistence of those SNPs. Our results provide important implications for developing effective malaria vaccines and better understanding of acquired immunity against falciparum malaria.
恶性疟原虫（Plasmodium falciparum）是最致命的人类疟疾寄生虫，由于感染的广泛传播和地方性，其种群呈现出多样性。疟原虫抗原在寄生虫种群内和种群间的遗传多样性仍然是疟疾发病机制以及候选疫苗临床试验的一个令人困惑的因素。寄生虫种群中靶抗原的变异可能是由于免疫压力引起的，这取决于获得性免疫的水平。或者，与我们在管家基因方面的研究类似[Tanabe 等人，《当代生物学》2010;70:1-7]，候选疫苗抗原的种群内遗传多样性也可能取决于与假定的中非起源地的地理距离。为了解决这个问题，我们从非洲、东南亚和大洋洲的七个地理上多样化的寄生虫种群中获得了全长疟原虫基因的序列，包括顶膜抗原 1（ama1）（n=459）、环子孢子蛋白（csp）（n=472）和裂殖子表面蛋白 1（msp1）（n=389）；并与之前确定的序列（csp 和 msp1 分别为 n=13 和 n=15）一起分析了种群内单核苷酸多态性（SNP）多样性。这三个抗原基因的 SNP 多样性支持了隔离遗传距离的模型。每个位点的多态性位点标准化数（θ(S)）表明，77-83%可以归因于与非洲起源地的地理距离，这表明地理距离在靶候选疫苗抗原的变异中起着重要作用。此外，我们观察到抗原基因中的大量 SNP 在非洲和非非洲寄生虫种群之间共享，表明这些 SNP 具有长期的持久性。我们的研究结果为开发有效的疟疾疫苗和更好地了解针对恶性疟原虫的获得性免疫提供了重要的启示。
