Study of epigenetic mechanisms related to relapses in vivax malaria

• Grant number: 24/12378-2
• Support Opportunities: Scholarships in Brazil - Support Program for Fixating Young Doctors
• Start date: August 01, 2024
• End date: July 31, 2025
• Field of knowledge: Biological Sciences - Parasitology
• Agreement: CNPq
• Principal Investigator: Fabio Trindade Maranhão Costa
• Grantee: Andressa Barban do Patrocinio
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 24/02019-5 - Study of epigenetic mechanisms related to relapses in vivax malaria, AP.R

Abstract

Malaria is one of the neglected diseases with major extent in the world and is caused by Plasmodium spp. parasites. In Brazil, Plasmodium vivax is responsible for 85% of the disease cases. Thus, vivax malaria is a public health problem in developing countries, mainly in Brazil, and the infection caused by this parasite is considered a Tropical Neglected Disease by the World Health Organization. Despite recent advances in the control of malaria cases in Brazil, especially P. falciparum, the control of vivax malaria is still a persistent and challenging obstacle. This difficulty is based on the fast onset of sexual evolutionary stages transmitted by the mosquito., as well as the existence of dormant hepatic forms, called hypnozoites. Activation of hypnozoites is responsible for disease relapses, presenting clinical symptoms again in patients without the host being bitten by an infected mosquito. In this context, Prof. Fabio TM Costa's laboratory has recently started an original and ambitious project financed by renowned funding agencies (FAPESP, CNPq e Bill & Melinda Gates Foundation). This study involves the recruitment of over 300 vivax malaria patients in the Amazon, presenting or not relapsing episodes. The rational of this study is to identify, using omics, a molecular biosignature capable of mapping relapse susceptibility and risks, as well as associated mechanisms. Preliminary metabolomic results showed alterations in two molecules linked to epigenetic changes, methyldeoxycytidine and sphingosine 1-phosphate, suggesting possible participation of epigenetic mechanisms in this process, i.e., how chromatin states affect parasite and host transcriptomes. Therefore, the project will be conducted in four phases: I. Analyze chromatin accessibility by ATAQ-seq to map the chromatin access regions and the genes that are in these regions.II. Identifying chromatin signatures of parasites, from samples from patients with potential and non-relapse, to identify epigenetic signatures of the parasite related to relapse of vivax. III. The. 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 us to detect the biochemical pathways affected by the artificial epigenetic change caused by the inhibitor, aiming to identify possible therapeutic targets.. IV. Integrating epigenome data (ATAC-seq) and other omics data already being carried out in the group to search for relapse mechanisms and biomarkers, in addition to possible biochemical pathways relevant for treatment. (AU)