Dissecting the mechanisms of infectivity in Plasmodium - Plasmodium yoelii experimental model with implications for the study in Plasmodium vivax.

Abstract

Plasmodium vivax is responsible for more than 80 million cases of malaria worldwide each year, with strong social impact outside of the African continent especially in Asia and in the Americas. Moreover, recently it was found that similarly to infection by P. falciparum infections by P. vivax can also progress to severe forms of the disease. The whole invasion process is complex and involves multiple interactions between parasite ligands and erythrocyte receptors in a coordinated manner. Current knowledge of the mechanisms and interactions during invasion of erythrocytes by the parasite are limited and this interfers with the development of approaches to block this essential pathway essencial for Plasmodium life cycle. Strategies capable of blocking the invasion of erythrocytes are part of the rational for many vaccines based on merozoite antigens. Accordingly, methodologies to elucidate the phenomenon of invasion could facilitate the validation and identification of potential antigens that could be used as targets in the development of vaccines. Studies related to the biology of P. vivax , its pathogenesis and infectivity is still poor, mainly due to the difficulty of continuous cultivation of this parasite and the restriction of the studies to hospital centers in malaria-endemic areas and laboratories with adequate infrastructure. P. vivax and P. yoelii both use antigen/receptor Duffy for chemokines (DARC) as a receptor for invasion and preferably invade reticulocytes. Furthermore, as P. yoelii shows an alternative route of infection, presumably DARC independent to invade reticulocytes and P. vivax also has an unknown mechanism to invade DARC negative reticulocytes, it is plausible to believe that alternative routes of invasion may be shared by these two parasites. Thus, this project aims to expand the understanding of the mechanisms of pathogenesis and infectivity of Plasmodium using P. yoelii experimental model. Therefore, we intend to investigate ligand/receptor interactions, identifying potential parasite ligands and receptors of erythrocytes (reticulocytes or mature erythrocytes) involved in alternative routes of invasion. To this end, we intent to evaluate the infectivity of different P. yoelii 17X transfectants with surface proteins deleted (EBP DBL , MAEBL , AMA -1 , Py235 and RON -2) in erythrocytes and reticulocytes Duffy positive mice (Dfy+ / +) and Duffy negative (Dfy -/ - ). The evolution of infection resulting from different combinations of the new parasite populations with the target cells will be analyzed to characterize the populations of infected target cells. Moreover, to suggest an alternative route of invasion we will study the invasion of the parasite in Dfy -/ - erythrocytes treated with monoclonal antibodies specific for erythrocyte surface molecules.