Malaria Invasion Via Glycophorin B in Brazilian Isolates

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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.