Malaria in Brazil: RBC variants & parasite invasion

巴西的疟疾：红细胞变异

• 批准号: 7913592
• 负责人: Sara Lustigman
• 金额: $ 31.56万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913592
• 关键词: Admixture; Alleles; Antigens; Area; Binding; Biological Assay; Blood Group Antigens; Brazil; Case-Control Studies; Cell surface; Cells; Characteristics; Comparative Study; Contracts; Control Groups; Country; Dependence; Development; Enzymes; Erythrocytes; Ethnic Origin; Falciparum Malaria; Family; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glycophorin; Glycophorin A; Glycophorin B; Goals; Haplotypes; Hybrids; Immune response; In Vitro; Individual; Infection; Invaded; Laboratories; Life; Ligands; Linkage Disequilibrium; Malaria; Measures; Molecular; Morbidity - disease rate; Neuraminidase; PAR-2 Receptor; Parasites; Pathway interactions; Phenotype; Plasmodium falciparum; Population; Positioning Attribute; Predisposition; Process; RH1; Resistance; Risk; Site; Specificity; Structure; Subgroup; Surface; Testing; Time; Trypsin; Vaccines; Variant; base; case control; chymotrypsin; field study; flexibility; meetings; novel; parasite invasion; prospective; receptor; vaccine candidate; vaccine development

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.

越来越多的证据表明，获得疟疾和发病率的风险由宿主确定 遗传因素和感染寄生虫菌株的基因型。这项研究的主要目标是改善 了解多态性在RBC受体中的影响，特别是糖蛋白B（GPB），以及 寄生虫的寄生虫的侵略配体变体对所使用的各种入侵途径的影响 在巴西亚马逊两个地方性地区的恶性疟原虫。恶性疟原虫入侵 通过使用不同的RBC受体的几种途径，其中包括糖蛋白（GPA，GPB和 GPC），Band 3和其他尚未确定的身份。 RBC的特异性取决于连接受体 相互作用及其在恶性疟原虫中不是静态的，部分是为了为寄生虫提供更大的灵活性。 与这些途径具有的实验室分离株相比，现场分离株可能显示出更大的可变性 被定义。该应用的基本假设是宿主和寄生虫遗传因素既可以 驱动恶性疟原虫内人群区域中不同的RBC入侵途径的出现。更好地理解 这一过程中涉及的宿主和寄生虫因素的贡献，我们将研究高度混合的巴西人 亚马逊人口及其暴露的寄生虫。我们的最初研究表明 GPB S变体在患有恶性疟原虫感染的个体中更频繁 巴西。此外，我们发现亚马逊分离株的入侵配体有限 与实验室菌株相比，它们表达了独特的变体，其中一些与 相应场分离株的定义入侵概况。为了更好地了解恶性疟原虫的RBC入侵 在现场并确定寄生虫配体与RBC受体之间的分子相互作用是否 在实验室分离株中观察到的与该领域中的疟疾感染有关：1） 为了确定GYPB基因中的分子变异，尤其是生成GYPB*S/S的分子变异 等位基因，影响宿主在两个截然不同的巴西亚马逊内部人群中与恶性疟原虫感染的易感性 地区。将比较各种GYPB变体的等位基因和单倍型频率 在每个内在位点以及站点之间的种族匹配的病例和对照组。 2）确定 确定的GYPB多态性对巴西亚马逊田间隔离的RBC入侵的影响 主要使用GPB入侵途径。 3）研究恶性疟原虫配体之间的关联 亚马逊田地隔离株和/或能力的多态性和RBC入侵概况 具有定义表型与RBC结合的变体配体。我们的研究可能会更加关注GPB 作为现场分离株入侵的重要RBC受体，并激励寻找GPB寄生虫配体 然后，这也可能成为重要的疫苗候选者。我们的研究也可能影响 针对恶性疟原虫疟疾的全球疫苗，该疫苗的靶向多重决定了梅罗洛伊特的侵袭。