Malaria in Brazil: RBC variants & parasite invasion

越来越多的证据表明，感染疟疾的风险和发病率取决于宿主 遗传因素和感染寄生虫菌株的基因型。本研究的主要目的是更好地 了解红细胞受体多态性，特别是血型糖蛋白B（GPB），以及 寄生虫的侵袭配体变体库对所使用的各种侵袭途径的影响 恶性疟原虫在巴西亚马逊河流域的两个地方病流行区。恶性疟原虫的裂殖子侵入 通过使用不同RBC受体的几种途径，包括血型糖蛋白（GPA，GPB和 GPC）、Band 3和身份尚未确定的其他人。红细胞特异性依赖于配体和受体 这些相互作用在恶性疟原虫中不是静态的，部分原因是为寄生虫提供了更大的灵活性。 田间分离株可能比实验室分离株表现出更大的变异性，在实验室分离株中，这些途径具有 被定义。本申请的基本假设是宿主和寄生虫的遗传因素都可能 在恶性疟原虫流行地区，红细胞入侵途径的出现。更好地了解 在这一过程中所涉及的主机和寄生虫因素的贡献，我们将研究高度混合巴西 亚马逊人口和他们所接触的寄生虫。我们的初步研究表明， GPB S变异在两个流行区的恶性疟原虫感染者中更常见， 巴西此外，我们发现，亚马逊分离物具有有限的入侵配体库， 与实验室菌株相比，它们表达独特的变体，其中一些与 确定了相应田间分离株的入侵概况。为了更好地了解恶性疟原虫对红细胞的侵袭， 并确定寄生虫配体和红细胞受体之间的分子相互作用 在实验室中观察到的分离株与实地疟疾感染有关，提出以下目标：1） 为了确定GYPB基因的分子变异，特别是产生GYPB*S/s的基因， 等位基因，影响宿主感染恶性疟原虫的易感性，在两个不同的巴西亚马逊地方病 地区不同GYPB变异体的等位基因和单倍型频率将在不同年龄组之间进行比较。 在每个流行地点内和地点之间的种族匹配的病例组和对照组。2)确定 确定GYPB多态性对巴西亚马逊野外分离物亚群RBC侵袭的影响， 主要使用GPB入侵途径。3)研究恶性疟原虫配体与 多态性和亚马逊野外分离株使用的RBC侵袭谱和/或 变体配体结合具有确定表型的RBC。我们的研究可能会使人们更加关注GPB GPB作为一种重要的红细胞受体，在野外分离株入侵中发挥重要作用，并促使人们寻找GPB寄生虫配体 这也可能成为重要的候选疫苗。我们的研究也可能影响 针对恶性疟原虫疟疾的全球疫苗，靶向裂殖子入侵的多个决定因素。

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.