Parasites in the genus Plasmodium, which cause malaria, are transmitted to humans through bites from infected mosquitoes. The parasites manage to acclimatize to these two completely different hosts because the plasticity of their genome enables them to adapt as necessary. Scientists at the Institut Pasteur and the CNRS decided to investigate the epigenetic mechanisms behind this plasticity, in particular DNA methylation. They identified molecules capable of inhibiting DNA methylation and effectively killing even the most resistant Plasmodium falciparum parasites. The results of their research were published on November 27, 2019 in the journal ACS Central Science.

Plasmodium falciparum/CDC

Malaria affects more than 200 million people worldwide every year, and resistance to antimalarial treatments is constantly increasing. This infectious disease is caused by Plasmodium parasites that are capable of adapting to varied environments. During the parasite’s life cycle, it lives in the salivary glands of the mosquito vector before infecting the liver and then the blood of the human host. “At each stage in the cycle, epigenetic mechanisms such as histone or DNA modifications regulate the expression of the parasite’s genes, enabling the specific expression of some genes in the cell at a given time so that the parasite can adapt to its environment,” explains Flore Nardella, a contract researcher in the Biology of Host-Parasite Interactions laboratory (Institut Pasteur/CNRS/Inserm).

In 2019, her laboratory, led by CNRS scientist Artur Scherf, demonstrated the importance of epigenetic DNA modifications for the parasite’s life cycle. The Institut Pasteur’s Epigenetic Chemical Biology laboratory has unparalleled expertise in the field of DNA methyltransferase inhibitors. So it was logical for the two teams to work together to identify molecules capable of inhibiting DNA methylation and killing parasites. “Artur’s team had a thorough knowledge of the epigenetic mechanisms in malaria, and we had an original chemical library with inhibitors that had already been optimized for these modifications,” explains Paola B. Arimondo, a chemist, CNRS Director of Research and Head of the Epigenetic Chemical Biology Unit (Institut Pasteur/CNRS).

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