Genetic polymorphisms in malaria vaccine candidate Plasmodium falciparum reticulocyte-binding protein homologue-5 among populations in Lagos, Nigeria
Genetic polymorphisms in malaria vaccine candidate Plasmodium falciparum reticulocyte-binding protein homologue-5 among populations in Lagos, Nigeria
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DOI：
10.1186/s12936-019-3096-0
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发表时间：
2020-01-06
期刊：
影响因子：
3
通讯作者：
Amambua-Ngwa, Alfred
中科院分区：
文献类型：
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作者：
Ajibaye, Olusola;Osuntoki, Akinniyi A.;Amambua-Ngwa, Alfred
背景疫苗是引发针对疟疾的无菌免疫的最可靠替代方案，但其发展受到先前研究抗原的多态性和菌株特异性的阻碍。因此迫切需要新的候选疫苗。高度保守的恶性疟原虫网织红细胞结合蛋白同源物 5 (PfRH5) 已被确定为抗疾病疫苗开发的潜在候选者。 PfRH5 对于裂殖子侵入红细胞至关重要，并且对于寄生虫的生存至关重要。然而，关于恶性疟原虫现场分离株中 PfRH5 遗传变异程度的数据很少。这项研究描述了尼日利亚恶性疟原虫分离株中 PfRH5 的高亲和力结合多肽 (HABP) 36718、36727、36728 的遗传多态性。这项研究测试了这样的假设：只有 PfRH5 HABP 上特定的保守 B 和 T 细胞表位对疫苗开发至关重要。方法在对尼日利亚拉各斯三个不同人群的一项前瞻性横断面研究中收集了 195 个经显微镜证实的恶性疟原虫样本。使用双向测序方法确定 Pfrh5 基因的遗传多样性和单倍型构建。 Tajima's D 和非同义与同义突变的比率用于估计 pfrh5 基因中平衡和定向选择的程度。结果序列分析揭示了 PfRH5 的三种单倍型，其 Tajima's D 和 dN/dS 值分别为 -1.717 和 0.0110.020。观察到608位的单核苷酸多态性SNP(G→A)，导致203位的氨基酸半胱氨酸变为酪氨酸。单倍型和核苷酸多样性为0.318+/-0.016和0.0046+/-0.0001，而群体间遗传分化范围为0.007至0.037。鉴定出 5 种多肽变体，最常见的是 KTKYH，频率为 51.3%。研究中观察到了 1 个 B 细胞表位、151 个主要组织相容性复合物 (MHC) II 类 T 细胞表位、4 个本质上非结构化区域 (IUR) 和 6 个 MHC I 类 T 细胞表位。序列的系统发育分析显示了与 3D7、PAS-2 和 FCB-2 RH5 序列的聚类和进化关系的证据。 结论 p id=Par 这项研究揭示了尼日利亚拉各斯 PfRH5 基因沿线的本质非结构化区域中 PfRH5 抗原与 B 和 T 细胞表位的遗传多态性水平较低。然而，该国其他地区需要进行更广泛的调查，以支持将 PfRH5 纳入交叉保护性多成分疫苗的可能性。
BackgroundVaccines are the most reliable alternative to elicit sterile immunity against malaria but their development has been hindered by polymorphisms and strain-specificity in previously studied antigens. New vaccine candidates are therefore urgently needed. Highly conserved Plasmodium falciparum reticulocyte-binding protein homologue-5 (PfRH5) has been identified as a potential candidate for anti-disease vaccine development. PfRH5 is essential for erythrocyte invasion by merozoites and crucial for parasite survival. However, there is paucity of data on the extent of genetic variations on PfRH5 in field isolates of Plasmodium falciparum. This study described genetic polymorphisms at the high affinity binding polypeptides (HABPs) 36718, 36727, 36728 of PfRH5 in Nigerian isolates of P. falciparum. This study tested the hypothesis that only specific conserved B and T cell epitopes on PfRH5 HABPs are crucial for vaccine development.MethodsOne hundred and ninety-five microscopically confirmed P. falciparum samples collected in a prospective cross-sectional study of three different populations in Lagos, Nigeria. Genetic diversity and haplotype construct of Pfrh5 gene were determined using bi-directional sequencing approach. Tajima's D and the ratio of nonsynonymous vs synonymous mutations were utilized to estimate the extent of balancing and directional selection in the pfrh5 gene.ResultsSequence analysis revealed three haplotypes of PfRH5 with negative Tajima's D and dN/dS value of -1.717 and 0.0110.020, respectively. A single nucleotide polymorphism, SNP (G -> A) at position 608 was observed, which resulted in a change of the amino acid cysteine at position 203 to tyrosine. Haplotype and nucleotide diversities were 0.318 +/- 0.016 and 0.0046 +/- 0.0001 while inter-population genetic differentiation ranged from 0.007 to 0.037. Five polypeptide variants were identified, the most frequent being KTKYH with a frequency of 51.3%. One B-cell epitope, 151 major histocompatibility complex (MHC) class II T-cell epitopes, four intrinsically unstructured regions (IURs) and six MHC class I T-cell epitopes were observed in the study. Phylogenetic analysis of the sequences showed clustering and evidence of evolutionary relationship with 3D7, PAS-2 and FCB-2 RH5 sequences.Conclusions p id=Par This study has revealed low level of genetic polymorphisms in PfRH5 antigen with B- and T-cell epitopes in intrinsically unstructured regions along the PfRH5 gene in Lagos, Nigeria. A broader investigation is however required in other parts of the country to support the possible inclusion of PfRH5 in a cross-protective multi-component vaccine.