Malaria Epigenetics

Malaria is a preventable and treatable disease, yet it continues to claim an unacceptable number of lives every year, mainly among young children. The protozoan parasite Plasmodium falciparum causes the vast majority of malaria cases and deaths. We investigate this parasite with the strong believe that a deeper understanding of its biology will drive the development of new public health tools to combat the devastating disease that it produces.

Our team investigates the regulation of gene expression in P. falciparum (i.e., how the parasite uses its genes), with a special focus on epigenetic processes. Epigenetic regulation of gene expression in malaria parasites is linked to heterochromatin (a repressive type of chromatin). Genes regulated by heterochromatin are expressed in a clonally variant manner (i.e., different individual parasites express these genes differently). These genes play a fundamental role in the adaptation of parasite populations to changes in their environment.

We combine genome-wide approaches with studies on specific genes that control important processes in parasite biology. Among these, we are especially interested in the genes that regulate sexual conversion and the heat-shock response. Sexual conversion determines the balance between asexual replication in the same host, associated with disease, and conversion into sexual forms (gametocytes), which are necessary for malaria transmission. The heat-shock response enables parasite survival at febrile temperatures, which are the most characteristic clinical symptom of malaria. 

Lines of Research

1. Characterization of the epigenetic mechanisms that control sexual conversion in malaria parasites: malaria parasites undergo repeated cycles of asexual multiplication within the blood of their vertebrate hosts, but transmission to another host via a mosquito vector requires that some parasites convert into sexual forms termed gametocytes. We and others recently identified ap2-g as the master regulator that controls the switch from asexual growth to sexual development. The expression of this gene is regulated by heterochromatin. Using ap2-g as a marker, we have recently identified alternative pathways for sexual conversion, identified several conditions that enhance sexual conversion, and developed an inducible system for massive sexual conversion that we used to characterise at the multi-omic level early sexual stages. We are currently investigating the regulation of gdv1, an upstream activator of ap2-g. The regulation of gdv1 involves heterochromatin-euchromatin transitions, a complex regulatory loop and newly identified factors.

2. The malarial heat-shock response: we recently described an ApiAP2 transcription factor, which we termed PfAP2-HS, that is the master regulator of the protective heat shock response. This is, to our knowledge, the first identification of a malarial transcription factor that activates a directed transcriptional response to changes in the environment. Of note, fever is the most characteristic clinical symptom of malaria, so parasites are frequently exposed to febrile temperatures to which they must adapt in order to survive. We have identified the targets of PfAP2-HS and determined its basic mode of action. We are currently investigating additional mechanistic aspects of the malarial heat-shock response and its role in parasite survival under stress conditions different from heat-shock, including drug pressure.

3. Plasmodium falciparum heterochromatin: we recently demonstrated that the malaria parasite P. falciparum regulates at the epigenetic level the expression of a multitude of genes that participate in important host-parasite interactions (clonally variant genes). We and others have established that heterochromatin-euchromatin transitions underlie the epigenetic regulation of these genes. We combine biochemical, epigenomic and genetic approaches to investigate additional aspects of heterochromatin biology in malaria parasites, including the determinants of where in the genome heterochromatin is formed.

4. Adaptation of malaria parasites to changes in their environment using bet-hedging strategies: spontaneous P. falciparum transcriptional variation plays a central role in malarial host-parasite interactions by controlling important processes such as antigenic variation, sexual conversion, solute uptake or erythrocyte invasion. Our previous work identified gene families with variant expression in P. falciparum and revealed that adaptation to fluctuating conditions can occur via bet-hedging strategies. We aim to characterize additional conditions of the environment to which parasites can adapt using clonally variant gene expression.

Selected Papers

• S. Nhim, E. Tintó-Font, N. Casas-Vila, L. Michel-Todó & A. Cortés, 2024, “Heterochromatin dynamics during the initial stages of sexual development in Plasmodium falciparum”, Sci. Rep. 14:23180.
• L. Michel-Todó, C. Bancells, N. Casas-Vila, N. Rovira-Graells, C. Hernández-Ferrer, J.R. González & A. Cortés, 2023, “Patterns of Heterochromatin Transitions Linked to Changes in the Expression of Plasmodium falciparum Clonally Variant Genes”, Microbiol Spectr. 11:e0304922.
• E. Tintó-Font & Cortés A., 2022, News & Views: “How a malaria parasite becomes a male”, Nature 612:408-409.
• H.P. Portugaliza, H.M. Natama, P. Guetens, E. Rovira-Vallbona, A.M. Somé, A. Millogo, D.F. Ouédraogo, I. Valéa, H. Sorgho, T. Halidou, N. van Hong, A. Sitoe, R. Varo, Q. Bassat, A. Cortés* & A. Rosanas-Urgell*, 2022, “Plasmodium falciparum sexual conversion rates can be affected by artemisinin-based treatment in naturally infected malaria patients”, EBioMedicine 83:104198. *equal contribution, co-corresponding authors

• E. Tintó-Font, L. Michel-Todó, T.J. Russell, N. Casas-Vila, D.J. Conway, Z. Bozdech, M. Llinás & A. Cortés, 2021, “A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures”, Nature Microbiology 6:1163-74.
• A.K. Pickford, L. Michel-Todó, F. Dupuy, A. Mayor, P.L. Alonso, C. Lavazec & A. Cortés, 2021, “Expression patterns of Plasmodium falciparum clonally variant genes at the onset of a blood infection in malaria-naive humans”, mBio 12:e01636-21.
• H.P. Portugaliza, S. Miyazaki, F.J. Geurten, C. Pell, A. Rosanas-Urgell, C.J. Janse & A. Cortés, 2020, “Artemisinin exposure at the ring or trophozoite stage impacts Plasmodium falciparum sexual conversion differently”, eLife 9:e60058.
• O. Llorà-Batlle, L. Michel-Todó, K. Witmer, H. Toda, C. Fernández-Becerra, J. Baum & A. Cortés, 2020, “Conditional expression of PfAP2-G for controlled massive sexual conversion in Plasmodium falciparum”, Science Advances 6:eaaz5057.
• C. Bancells, O. Llorà-Batlle, A. Poran, C. Nötzel, N. Rovira-Graells, O. Elemento, B.F.K. Kafsack & A. Cortés, 2019, “Revisiting the initial steps of sexual development in the malaria parasite Plasmodium falciparum”, Nature Microbiology 4:144-54.
• B.F.C. Kafsack, N. Rovira-Graells, T.G. Clark, C. Bancells, V.M. Crowley, S.G. Campino, A.E. Williams, L.G. Drought, D.P. Kwiatkowski, D.A. Baker, A. Cortés & M. Llinás, 2014, “A transcriptional switch underlies commitment to sexual development in malaria parasites”, Nature 507:248-52.
• N. Rovira-Graells, A.P. Gupta, E. Planet, V.M. Crowley, S. Mok, L. Ribas de Pouplana, P.R. Preiser, Z. Bozdech & A. Cortés, 2012, “Transcriptional variation in the malaria parasite Plasmodium falciparum”, Genome Research 22:925-38.

Here you will find all publications:

Selected Projects

• "Mechanisms of the transcriptional responses to changes in the environment in the malaria parasite Plasmodium falciparum (RESPONSE)” (2023-2026). “Proyectos de Generación de Conocimiento” grant (PID2022-137863OB-I00), Spanish Ministry of Science and Innovation (MICIN) / Agenica Estatal de Investigación (AEI).
• “Characterization of PfAP2-R (Ring): an essential AP2-DNA binding protein required for ring stage development during Plasmodium falciparum intra-erythrocytic developmental cycle” (2023-2025). Unfunded Collaborator in an “Opportunity Fund Program” (OFP) 2023 pilot grant (Saudi Arabia). Principal Investigator: Prof. Arnab Pain (KAUST).
• “Host immune and metabolic determinants of sexual conversion in Plasmodium parasites” (2023-2026). Co-Promoter (co-PI) for a Research Foundation – Flanders (FWO, Belgium) grant (IMMETASEX, G067823N). Principal Investigator: Prof. Anna Rosanas-Urgell.