Study of epigenetic mechanisms related to relapses in vivax malaria

• Grant number: 24/02019-5
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Agreement: CNPq
• Principal Investigator: Fabio Trindade Maranhão Costa
• Grantee: Fabio Trindade Maranhão Costa
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/18611-7 - Development of new tools for search and validation of molecular targets for therapy against Plasmodium vivax, AP.TEM
• Associated scholarship(s): 24/12378-2 - Study of epigenetic mechanisms related to relapses in vivax malaria, BP.JD

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 disease cases. 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 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 rapid onset of sexual evolutionary stages transmitted to the mosquito, as well as the existence of dormant hepatic forms, called hypnozoites. Activation of hypnozoites is responsible for disease relapses, with the reappearance of clinical symptoms 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, through omics, a biosignature capable of mapping relapse susceptibility and risks, as well as associated mechanisms. Preliminary metabolomic results show 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) Analyzing chromatin accessibility by ATAQ-seq to map chromatin access regions and the genes that are in these regions; (II) Determining possible modifications in parasite chromatin, originating from samples of patients with and without relapse, aiming to identify parasite epigenetic signatures related to vivax malaria relapse; (III) a. Unraveling the epigenetic mechanism involved in relapse episodes through functional analyses with in vitro incubation of histone modifying enzyme inhibitors in both host (PBMCs) and parasite (whole blood); b. Performing iTRAQ quantitative proteome assays. These analyses will allow us to detect biochemical pathways affected by the artificial epigenetic change caused by the inhibitor, aiming to identify possible therapeutic targets, and (IV) Comparing the epigenetic findings in items I, II and III, against transcriptome, proteomics and metabolomics analyses that are in progress, in order to identify molecules involved in the epigenetic plasticity of the parasite-host relationship. We believe those findings can impact in the design of new pharmacological and diagnostic intervention strategies in vivax malaria. (AU)