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Approaching the role of three ApiAP2 transcription factors in the control of gene transcription in intraerythrocytic and sexual stages of Plasmodium falciparum

Grant number: 16/12659-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2017
Effective date (End): November 25, 2020
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Gerhard Wunderlich
Grantee:Eliana Fernanda Galindo Cubillos
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):19/16129-9 - Functional study of ApiAP2 transcription factors during Plasmodium falciparum sexual stages, BE.EP.DR

Abstract

The protozoan parasite Plasmodium falciparum causes the most severe form of human malaria and the most vulnerable persons are children under the age of 5 years and pregnant women. To evade the constantly evolving host immune response to infection, asexual parasite forms use antigenic variation of virulence-associated genes and sexual differentiation as a strategy to survive and secure their transmission to the mosquito. The molecular basis behind this process is still poorly understood and until now a number of chromatin modifying enzymes were implied in the process of antigenic variation but also induction gametocyte formation. However, it is not known how the parasite orchestrates these phenomena as well as the mechanisms that trigger these processes and which transcription factors are possibly involved. In this project, we propose to address the participation of three putative ApiAP2 transcription factors (TFs), PF3D7_1143100, PF3D7_1466400 and PF3D7_1007700, in the control of gene transcription in the intraerythrocytic and sexual stages of P. falciparum. We attempt to investigate the loss of function effect of these proteins on the blood stage development and mosquito stage, by comparison of two conditions, "ON" and "OFF" for the expression of each target protein. This will be done using genetically modified parasites lines which either i) have the determined ApiAP2 proteins C-terminally tagged with a destabilizing domain which then can be stabilized through the incubation of parasites with a small molecule, or ii) have a 3' localized ribozyme sequence (glmS) included in the ApiAP2 transcripts, both of which then turn the targeted protein or transcript regulatable. Since the proteins of interest will also be tagged with an HA tag we will be able identify by Chip-Seq the specific genomic loci that these TFs are binding to. This study will contribute novel information about the transcription control in P. falciparum, and will probably point to novel drug targets since i) the interference of a possible key process for the parasites survival makes them more vulnerable and ii) the ApiAP2 transcription factors are absent in the human host. (AU)