Last Updated: 15/10/2025
Mechanisms of transcriptional responses to changes in environmental conditions in the malaria parasite Plasmodium falciparum
Objectives
This project aims at studying how the parasite detects heat stress, activates PFAP2-HS, and increases transcription of its target genes.
Hypothesis 1: regulation of PFAP2-HS activation involves chaperone displacement and phosphorylation, as occurs with HSF1.
- determine whether other proteotoxic conditions, such as artemisinin treatment, can activate the PFAP2-HS-regulated heat shock response, and whether this pathway plays a role in artemisinin resistance;
- characterize the proteomic changes that occur during the heat shock response and investigate the alterations in nucleolar organization and chromosome contacts associated with this response; and
- investigate the role of different PFAP2-HS domains in these processes.
This project will also investigate the mechanisms of GDV1 activation under different environmental conditions.
Hypothesis 2: different conditions that increase the sex conversion rate produce changes in the same metabolites, and these affect the heterochromatin of the GDV1 gene.
- characterize GDV1 activation, which involves messenger RNA and antisense RNA, at the individual cell level, and study whether the activation mechanism involves changes in chromosome contacts.
The parasite Plasmodium falciparum causes the most severe forms of human malaria. The blood stages of the parasite, which include asexual parasites and sexual precursors called gametocytes, are responsible for the clinical symptoms of malaria and transmission to mosquitoes, respectively. Like all organisms, P. falciparum must adapt to changes in its environmental conditions. Although human blood circulation conditions are relatively stable, there are important fluctuations to which the parasite needs to adapt using different strategies.
Recent studies have shown that P. falciparum produces protective transcriptional responses when exposed to temperature conditions that mimic fever episodes (the most characteristic symptom of malaria), low levels of phospholipid precursors, or drugs such as artemisinin. In the case of febrile temperatures, the parasite responds by activating the expression of a small group of genes that encode chaperones through the transcription factor PFAP2-HS. This response resembles the heat shock response regulated in other eukaryotes by the transcription factor HSF1, which is absent in malaria parasites. In conditions of low phospholipid precursor levels or exposure to artemisinin, the response involves activation of the regulator GDV1, which subsequently activates the transcription factor PFAP2-G and induces sex conversion (the transformation of asexual parasites into sexual ones). However, many aspects of these two response pathways remain uncharacterized.
Through the experiments conducted in this study, the project aims to elucidate the mechanistic steps in the P. falciparumresponse to high temperatures, from detection to transcriptional activation of target genes.
This research seeks to advance understanding of the regulation of the two principal transcriptional responses described thus far in P. falciparum, which enable the parasite to adapt to two common environmental conditions.
Jan 2022 — Dec 2026
$499,422
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