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，感染疟疾的风险和发病率由宿主决定。 遗传因素和感染寄生虫菌株的基因型别。这项研究的主要目标是更好地 了解RBC受体，特别是血糖素B(GPB)的多态以及 寄生虫的入侵配体变异体对所使用的多种入侵途径的影响 在巴西亚马逊的两个流行地区被恶性疟原虫感染。恶性疟原虫裂殖子入侵 通过使用不同的RBC受体的几种途径，其中包括血糖素(GPA、GPB和 GPC)、Band 3和其他身份尚未确定的人。RBC的特异性依赖于配体受体 在恶性疟原虫中，这些相互作用并不是静态的，部分原因是为寄生虫提供了更大的灵活性。 野外分离株可能表现出比这些途径中的实验室分离株更大的变异性 已经被定义了。这一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区出现不同的红细胞入侵途径。为了更好地理解 寄主和寄生虫因素在这一过程中的贡献，我们将研究高度混杂的巴西 亚马逊人口和他们所接触的寄生虫。我们的初步研究表明， 在中国两个恶性疟原虫流行区感染恶性疟原虫的个体中，GPB S变异更为常见 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基。 与实验室菌株相比，它们表达独特的变体，其中一些与 定义了相应野外分离物的入侵特征。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RBC受体之间的分子相互作用 在实验室中观察到的分离株与现场疟疾感染有关，提出了以下目标：1) 确定GYPB基因，特别是产生GYPB的基因是否存在分子变异*S/S 在两个不同的巴西亚马逊地方性疾病中，等位基因影响宿主对恶性疟原虫感染的易感性 地区。不同GYPB变异的等位基因和单倍型频率将在 在每个流行地点内和地点之间，种族匹配的病例组和对照组。2)确定 已定义的GYPB基因多态性对巴西亚马逊地区分离株RBC侵袭的影响 主要使用GPB侵袭途径。3)研究恶性疟原虫配体之间的相互关系 亚马逊野外分离物的多态和RBC入侵特征和/或 变异型配体与具有特定表型的红细胞结合。我们的研究可能会对GPB产生更大的关注 作为一种重要的RBC受体对野生菌的侵袭，并推动对GPB寄生虫配体的寻找 然后，它也可能成为重要的候选疫苗。我们的研究也可能影响到 针对裂殖子入侵多个决定因素的全球恶性疟疫苗。