Study of epigenetic mechanisms related to relapses in vivax malaria

Malaria is one of the most neglected diseases in the world and is caused by the parasite Plasmodium spp. In Brazil, Plasmodium vivax is responsible for around 85% of cases of the disease. Thus, vivax malaria is one of the biggest public health problems in developing countries, mainly in Brazil, and the infection caused by this parasite is considered a Neglected Disease by the World Health Organization. Despite recent advances in containing cases of malaria in Brazil, especially P. falciparum, control of vivax malaria is still a persistent and challenging obstacle. This difficulty is based on the rapid appearance of sexual evolutionary forms transmitted to the mosquito, as well as the existence of dormant liver forms, called hypnozoites. The activation of hypnozoites is responsible for relapses of the disease, with the reappearance of a clinical condition without the host having been bitten by an infected mosquito. In this sense, Prof.’s group. Dr. Fabio TM Costa recently started an original and ambitious project financed by renowned funding agencies (FAPESP, CNPq and Bill & Melinda Gates Foundation). This study involves the recruitment of more than 300 patients with vivax malaria from the Amazon, presenting (or not) relapse episodes. Preliminary metabolomics results show changes in two molecules related to epigenetic changes, methyldeoxycytidine and sphingosine 1-phosphate, which suggests a possible participation of epigenetic mechanisms in this process, that is, how chromatin states affect the parasite and host transcriptome. To this end, the project will be carried out in four stages: (I) Analyze chromatin accessibility by ATAQ-seq to map chromatin access regions and the genes that are in these regions; (II) Determine possible modifications in the chromatin of parasites, from samples from patients with and without relapse, to identify epigenetic signatures of the parasite related to relapse of vivax malaria; (III) a. Unravel the epigenetic mechanism involved in relapse episodes through functional analyzes with in vitro incubation of histone modifying enzyme inhibitors in both the host (PBMCs) and the parasite (whole blood);b. Perform iTRAQ quantitative proteome assays. These analyzes will allow the detection of the biochemical pathways affected by the artificial epigenetic change caused by the inhibitor, aiming to identify possible therapeutic targets and (IV); Compare the epigenetic findings in items I, II and III, against transcriptome, proteomics and metabolomics analyzes that are in progress, in order to identify molecules involved in the epigenetic plasticity of the parasite-host relationship. The belief is that these findings may impact the design of new pharmacological and diagnostic intervention strategies in vivax malaria.

Project details

Genetics and Genomics
P. vivax

Jul 2024 — Jun 2026

Brazil