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，获得感染和发生严重并发症的风险取决于宿主遗传因素和感染寄生虫菌株的基因型。FIRCA项目将重点研究恶性疟原虫merozoites通过糖蛋白B （GPB）介导的替代入侵途径侵入红细胞（rbc）。这项研究将主要在巴西进行，并与dr。来自巴西联邦大学Carlos Chagas Filho生物研究所的Zalis、Castilho和Machado；坎皮纳斯州立大学血液中心；和圣荷西医学院，分别作为NIH拨款P50 HL54459-06的延伸。他们在以下方面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，这对于深入了解恶性疟原虫入侵受体红细胞抗原是必要的。本研究的具体目的是建立GPB介导的入侵途径在巴西朗多尼亚韦柳港分离株中的应用。在该地区的初步研究表明，红细胞上GPB S等位基因的存在与疟疾易感性有关，而GPB S等位基因的缺失与疟疾感染耐药性有关，这表明来自该特定地区的寄生虫更频繁地使用GPB。在印度或冈比亚进行的入侵研究没有确定GPB是否被这些野外分离株用于入侵。巴西科学家将进行三项核心研究：(1)确定恶性疟原虫野区分离物使用不同的入侵途径，使用酶处理红细胞，从其表面切割确定的部分；(2)评估恶性疟原虫感染者和居住在该地区但未感染的人群中定义的GPB血型抗原的分布；(3)通过对具有明确GPB表型的细胞进行侵袭试验，验证不同GPB变异在GPB介导的侵袭途径中的重要性。该项目将最终支持宿主红细胞受体和寄生虫入侵配体的相互作用如何影响巴西流行地区恶性疟原虫的进入途径的理解。由于每种入侵途径及其相应的配体都是疫苗的靶标，因此它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.