Malaria Invasion Via Glycophorin B in Brazilian Isolates

描述（由申请人提供）：疟疾是最严重和最广泛的人类寄生虫病。越来越多的证据表明，获得感染和发展严重并发症的风险由宿主遗传因素和感染寄生虫株的基因型决定。FIRCA项目将重点关注恶性疟原虫裂殖子通过血型糖蛋白B（GPB）介导的替代侵入途径侵入红细胞（RBC）。这项研究将主要在巴西进行，分别与来自里约热内卢联邦大学生物研究所卡洛斯·查加斯菲略、坎皮纳斯州立大学血液中心和圣何塞杜里奥普雷托医学院的Zalis、Castilho和马查多博士合作，作为NIH资助P50 HL 54459 - 06的扩展。他们带来了宝贵的专业知识：（a）分子寄生虫学，专门关注疟疾现场分离株，（B）免疫血液学，这是深入了解红细胞抗原所必需的，红细胞抗原是恶性疟原虫入侵的受体。本研究的具体目的是建立使用GPB介导的途径，从韦略港，Rondonia的巴西分离株的入侵。该地区的初步研究表明，GPB S等位基因在红细胞上的存在与易感性有关，而其缺失与抗疟疾感染有关，这表明GPB被来自该特定地区的寄生虫更频繁地使用。在印度或冈比亚进行的入侵研究没有确定GPB是否用于这些田间分离株的入侵。巴西科学家将进行三项核心研究：（1）使用经酶处理的红细胞，从红细胞表面切割确定的部分，确定恶性疟原虫现场分离株对不同入侵途径的使用;（2）评估确定的GPB血型抗原在恶性疟原虫感染者和生活在该地区但未感染者中的分布;和（3）使用对具有确定的GPB表型的细胞的侵袭测定来验证不同的GPB变体在GPB介导的侵袭途径中的重要性。该项目将最终支持了解宿主RBC受体和寄生虫入侵配体的相互作用如何影响巴西流行区恶性疟原虫的进入途径。由于每种入侵途径及其相应的配体都是疫苗的靶点，因此最终将有助于开发在巴西也有效的疫苗。

DESCRIPTION (provided by applicant): Malaria is the most serious and widespread human parasitic disease. A growing body of evidence indicates that the risk of acquiring infection and developing severe complications are determined by host genetic factors and the genotype of the infecting parasite strain. The FIRCA project will focus on the invasion of P. falciparum merozoites into red blood cells (RBCs) using alternative pathways of invasion and mediated by glycophorin B (GPB). The research will be done mostly in Brazil in collaboration with Drs. Zalis, Castilho and Machado from Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro; Hemocentro, State University of Campinas; and Faculdade de Medicina de Sao Jose do Rio Preto, respectively, as an extension of NIH grant P50 HL54459-06. They bring valuable expertise in: (a) molecular parasitology with a specialized focus on malarial field isolates, and (b) immunohematology, which is necessary for the in-depth knowledge of RBC antigens that are receptors for P. falciparum invasion. The specific aim of this study is to establish the use of GPB mediated pathway of invasion in Brazilian isolates from Porto Velho, Rondonia. Initial studies in this region have shown that the presence of the GPB S allele on the RBCs was associated with susceptibility while its absence was associated with resistance to malaria infection, suggesting that GPB is being used more frequently by the parasites from this particular region. Invasion studies done in India or The Gambia did not establish whether GPB was used for invasion by these field isolates. Three core studies will be undertaken by the Brazilian scientists: (1) To define the usage of different invasion pathways by P. falciparum field isolates using RBC treated with enzymes that cleave defined moieties from their surface; (2) To assess the distribution of defined GPB blood group antigens in P. falciparum infected individuals and in those who live in the region but are not infected; and (3) To validate the importance of distinct GPB variants in the GPB mediated invasion pathway using invasion assays into cells having defined GPB phenotypes. This project will ultimately support the understanding of how the interplay of host RBC receptors and parasite invasion ligand affects the route of entry of P. falciparum in an endemic area of Brazil. As each invasion pathway and their corresponding ligands are vaccine targets, it would ultimately aid in the development of vaccines that would be effective also in Brazil.