Malaria Invasion Via Glycophorin B in Brazilian Isolates

描述(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，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菌株的基因决定。FIRCA项目将重点研究恶性疟原虫裂殖子通过不同的入侵途径入侵红细胞，并由血糖素B(GPB)介导。这项研究将主要在巴西与里约热内卢联邦大学生物研究所的扎里斯、卡洛斯·查加斯·菲略博士、坎皮纳斯州立大学的Hemocentro博士和圣何塞大学的Faculdade de Medicina de Sao Jose do Rio Preto博士合作完成，作为NIH赠款P50 HL54459-06的延伸。它们带来了以下方面的宝贵专业知识：(A)分子寄生虫学，特别侧重于疟疾现场分离株；(B)免疫血液学，这是深入了解作为恶性疟原虫入侵受体的红细胞抗原所必需的。本研究的具体目的是建立利用GPB介导的侵袭途径在巴西罗多尼亚韦尔霍港分离株中的应用。该地区的初步研究表明，红细胞上GPB S等位基因的存在与易感性有关，而它的缺失与对疟疾感染的抵抗力有关，这表明该地区的寄生虫正在更频繁地使用GPB。在印度或冈比亚进行的入侵研究没有确定GPB是否用于这些野外分离株的入侵。巴西科学家将进行三项核心研究：(1)确定恶性疟原虫野外分离株使用经酶处理的红细胞的不同入侵途径；(2)评估定义的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的人中的分布；以及(3)通过对具有定义的GPB表型的细胞的入侵分析，验证不同的GPB变种在GPB介导的入侵途径中的重要性。该项目最终将有助于理解宿主红细胞受体和寄生虫入侵配体之间的相互作用如何影响恶性疟原虫在巴西流行地区的进入途径。由于每条入侵途径及其对应的配体都是疫苗靶标，这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.