Comparative study of Plasmodium vivax niches with emphasis on bone marrow and peripheral blood and their roles in the infection and pathology of this parasite

Abstract

Malaria caused by Plasmodium vivax is the most widely distributed form of the disease in the world. Currently, 2.5 billion people are at risk of infection with P. vivax, and in 2015 there were 8.5 million cases worldwide. Brazil, together with Venezuela, is the leader in cases in the Americas, with 99.5% of these reported in the region called Legal Amazon and, currently, more than 85% of cases in Brazil are caused by P. vivax. This Plasmodium species has several unique biological characteristics when compared to P. falciparum, such as: exclusive preference for reticulocyte infection; production of sexual stages (gametocytes) observed in the peripheral blood very early after infection; formation of hypnozoites (a latent stage that remains in the liver), which makes treatment difficult. Therefore, the same control measures used for P. falciparum have been shown to fail to control vivax malaria. Currently, P. vivax is considered a pathogen that causes severe immunopathological symptoms and an increase in the parasite's resistance to chloroquine has alarmed the scientific community. Furthermore, the impossibility of culturing the parasite in vitro for long periods, together with its particular characteristics, has challenged the understanding of the biology of this pathogen. In this proposal we intend to identify and characterize potential molecular targets of P. vivax to be used in chemotherapy strategies. Furthermore, we intend to verify the participation of molecules involved in endothelial disorders and evaluate potential inhibitors. More specifically, and considering the development of antimalarial drugs, we intend, through in silico analysis, to identify protein kinases (mainly) as molecular targets of P. vivax and establish a technological platform for the discovery of new drugs taking into account all stages of the parasite , including hypnozoites. We will have the participation of the recently established National Center for Research on Hypnozoites (FIOCRUZ-RJ), which provides models of non-human primates and P. cynomolgi infection, which will be used for evaluation of both drugs and experimental vaccines generated in the steps above. Furthermore, through P. vivax whole transcriptome next-generation sequencing (RNA-seq) and integrated data analysis, we hope to track new targets that by chance have not yet been considered in the pre-existing databases. Finally, we intend to evaluate plasma factors from infected patients capable of interfering with endothelial functions, as well as to test specific inhibitors in a murine infection model capable of inducing immunopathological complications.