Malaria in Brazil: RBC variants & parasite invasion

越来越多的证据表明，感染疟疾和发病的风险是由宿主决定的 遗传因素和感染寄生虫菌株的基因型。本研究的主要目标是更好地 了解红细胞受体多态性的影响，特别是血型糖蛋白 B (GPB) 以及 寄生虫的入侵配体变体库对所使用的入侵途径的多样性的影响 巴西亚马逊地区两个恶性疟原虫流行地区。恶性疟原虫裂殖子入侵 通过使用不同红细胞受体的多种途径，包括糖蛋白（GPA、GPB 和 GPC)、Band 3 和其他尚未确定身份的产品。红细胞特异性取决于配体受体 这些相互作用在恶性疟原虫中并不是静态的，部分原因是为了给寄生虫提供更大的灵活性。 现场分离株可能表现出比实验室分离株更大的变异性，其中这些途径具有 被定义。该应用的基本假设是宿主和寄生虫的遗传因素都可能 推动恶性疟原虫流行地区出现独特的红细胞侵袭途径。为了更好地理解 为了了解宿主和寄生虫因素在此过程中的贡献，我们将研究高度混合的巴西 亚马逊种群及其所接触的寄生虫。我们的初步研究表明 GPB S 变异在 2 个流行地区的恶性疟原虫感染个体中更为常见。 巴西。此外，我们发现亚马逊分离株在以下情况下具有有限的入侵配体库： 与实验室菌株相比，它们表达独特的变异，其中一些与 确定相应野外分离株的入侵概况。更好地了解恶性疟原虫对红细胞的侵袭 在现场确定寄生虫配体和红细胞受体之间是否存在分子相互作用 实验室分离株中观察到的菌株与实地疟疾感染相关，建议实现以下目标：1) 确定 GYPB 基因是否存在分子变异，特别是生成 GYPB*S/s 的基因 等位基因，影响两种不同的巴西亚马逊流行病宿主对恶性疟原虫感染的易感性 地区。各种 GYPB 变体的等位基因和单倍型频率将在 每个流行地点内以及地点之间种族匹配的病例组和对照组。 2）确定 确定的 GYPB 多态性对巴西亚马逊野外分离株亚群红细胞入侵的影响 主要利用GPB入侵途径。 3) 研究恶性疟原虫配体之间的关联 亚马逊野外分离株使用的多态性和红细胞入侵特征和/或 与具有确定表型的红细胞结合的变体配体。我们的研究可能会更加关注 GPB 作为野外分离株入侵的重要红细胞受体，并激发了对 GPB 寄生虫配体的研究 这也可能成为一种重要的候选疫苗。我们的研究也可能影响 针对裂殖子入侵的多个决定因素的针对恶性疟原虫疟疾的全球疫苗。

A growing body of evidence indicates that the risk of acquiring malaria and morbidity is determined by host genetic factors and the genotype of the infecting parasite strain. The major goal of this study is to better understand the impact that polymorphisms in RBC receptors, specifically glycophorin B (GPB), as well as the impact that the parasites¿ repertoire of invasion ligand variants have on the variety of invasion pathways used by P. falciparum in two endemic regions of the Brazilian Amazon. The merozoites of P. falciparum invade through several pathways using different RBC receptors, which include the glycophorins (GPA, GPB and GPC), Band 3 and others whose identity has not yet been determined. RBC specificity is dependent on ligandreceptor interactions and these are not static in P. falciparum, partly to provide greater flexibility to the parasite. Field isolates may show even greater variability than do the laboratory isolates in which these pathways have been defined. The underlying hypothesis of this application is that both host and parasite genetic factors may drive the emergence of distinct RBC invasion pathways in P. falciparum endemic regions. To better understand the contribution of host and parasite factors involved in this process, we will study the highly admixed Brazilian Amazon population and the parasites to which they are exposed. Our initial studies have shown that the GPB S variant is more frequent in individuals who have P. falciparum infection in two endemic regions in Brazil. Moreover, we found that the Amazonian isolates have limited repertoire of invasion ligands when compared to laboratory strains and that they express unique variants some of which are associated with a defined invasion profile of the corresponding field isolates. To better understand RBC invasion by P. falciparum in the field and determine whether the molecular interactions between parasite ligands and RBC receptors observed in laboratory isolates are relevant to malaria infection in the field the following aims are proposed: 1) To establish whether molecular variation in the GYPB gene, particularly the one that generates the GYPB*S/s alleles, influences host susceptibility to infection with P. falciparum in two distinct Brazilian Amazon endemic regions. The allelic and haplotypic frequencies of the various GYPB variants will be compared between ethnically matched case and control groups within each endemic site, and between sites. 2) To determine the impact of defined GYPB polymorphisms on RBC invasion by a subgroup of Brazilian Amazon field isolates that predominantly uses the GPB invasion pathway. 3) To study the association between P. falciparum ligand polymorphisms and the RBC invasion profiles used by the Amazonian field isolates and/or the ability of the variant ligand to bind to RBCs with defined phenotypes. Our studies will likely generate a greater focus on GPB as an important RBC receptor for field isolates invasion, and motivate the search for the GPB parasite ligand which could then become also an important vaccine candidate. Our studies could also impact development of global vaccines against P. falciparum malaria that target multiple determinants of merozoite invasion.