When the malaria parasite goes into hiding

Malaria is one of the most common communicable diseases in the world: every year, more than 200 million people are infected and almost half a million people die from it. While the disease spreads to humans mainly through mosquito bites, the underlying cause is the Plasmodium parasite.

The parasite can be killed by anti-malarial drugs, but these drugs are not effective at all stages of the parasite’s life cycle – in particular the dormant state, which scientists do not yet fully understand. Seeking to fill this gap in our knowledge, Hugo Frammery devoted his Master’s project to this particular aspect of the parasite's life. His work was supervised by Anush Chiappino-Pepe, a post-doc in Professor Vassily Hatzimanikatis’s Laboratory of Computational Systems Biotechnology (LCSB).

A little-known stage

The life cycle of the Plasmodium is relatively complex. “When an infected mosquito bites a human, the parasite finds its way to the liver where it penetrates cells known as hepatocytes,” says Frammery. Most of the parasites then reproduce and become encased in little packages called vesicles that subsequently enter the blood stream. Once there, they enter red blood cells, reproduce again and cause the red blood cells to burst. Every two or three days, all infected red blood cells erupt simultaneously. That’s what causes the fever spikes that are typical of malaria. Frammery notes, “In some Plasmodium species, between 5% and 15% of the parasites remain dormant in the liver cells. They do not reproduce and do not enter the blood stream. But after several months or even years, the parasites wake up and the cycle starts all over again.” Therein lies one of the particularities of malaria: even after being treated, patients are subject to recurring symptoms.

Reaching the dormant parasites is essential to eradicating malaria. “My goal was to characterize the parasite’s dormant state,” says Frammery. “If we can figure out how the parasite works, we can find a way to destroy it. So I used computational methods, feeding experimental lab data into a model that simulates the parasite’s metabolism. With this model, we can reconstruct all the chemical reactions that may take place inside the parasite.”

New drug targets

Frammery uses the model to test hypotheses of how the dormant malaria parasite functions. Refining the model and applying it to these hypotheses, it is possible to identify a number of activity zones in the parasite’s metabolism. Since the conditions required to activate a given path are known, it is possible to compare these results with experimental findings in order to confirm, or refute, the core hypothesis. If the hypothesis is confirmed, the model is considered realistic and its results can be used to move forward.The advantage of models is that they can simulate experiments much faster than labs can carry them out.

Yet this type of research also offers a mixed blessing: the quantity of results obtained. “We now have a huge amount of data to analyze to see whether any of our findings could lead to an effective drug therapy,” he adds. The idea is to identify everything that the parasite requires in the dormant state and that can be specifically destroyed without causing collateral damage. The ultimate goal is to either kill the dormant cells or wake them up so that they can be treated with drugs that work on the malaria parasite in its non-dormant state.

Project scope

This is the first time that computational modeling has been applied to the study of dormancy in microbes. The tools developed to learn more about malaria parasites could one day be used on other microorganisms that also have a dormant state. One such microorganism is the tuberculosis bacterium, which is carried by nearly a third of the world's population.

This project drew on the expertise of MalarX.ch, a consortium that includes the Universities of Geneva, Bern and Leiden, and the Wellcome Trust Sanger Institute.