Scientists at the University of Bern, Umeå University, and EPFL have for the first time systematically investigated the genome of the malaria parasite throughout its life cycle. The researchers identified hundreds of potential drug targets that are urgently needed to eradicate the disease.



Image: By combining a genome-wide screen with metabolic modeling, this study deciphers metabolic function and targets in the liver stage of the malaria parasite, offering a powerful crosshair (middle) to target the parasite liver stage (middle). Barcoded knockout parasites were followed through the parasite life cycle (fluorescent image of parasite liver stage), combining the findings with the computational analysis (code on the right) of a metabolic model (middle) to understand the liver stage development of Plasmodium parasites. Credit: Anush Chiappino-Pepe, Vassily Hatzimanikatis, Paul-Christian Burda, Volker T. Heussler

Despite great efforts in medicine and science, more than 400,000 people worldwide are still dying of malaria. The disease is transmitted by the bite of mosquitoes infected with the malaria parasite Plasmodium.

Plasmodium’s genome is relatively small, numbering about 5000 genes. Unlike humans, Plasmodium parasites only have a single copy of each gene, which means that removing one will cause a change in the phenotype of the parasite.

Now, an international consortium of scientists has taken advantage of this fact by carrying out a genome-wide gene deletion study on malaria parasites. Removing over 1300 individual genes, the scientists observed the effects of each deletion during the entire life cycle of the parasite and were thus able to identify many new targets in the pathogen.

The study was led by professors Volker Heussler at the University of Bern and Oliver Billker from Umeå University in Sweden, with the group of Vassily Hatzimanikatis at EPFL. It is published in the journal Cell.

Individual genetic codes accelerate research by decades

Each of the removed 1300 genes was replaced by an individual genetic code that allowed the scientists to study multiple parasites at the same time. This drastically shortened the time of the analysis: after only three years, they had systematically screened the genome of the parasite in all life cycle stages.

"The deletion screen, carried out jointly with the Sanger Institute, enabled us to identify hundreds of targets, particularly in the parasite's metabolism," says Rebecca Stanway (University of Bern), one of the study’s lead authors.

Model calculations extend experimental findings

To systematically analyze the large number of identified metabolic genes, the researchers joined forces with Professor Vassily Hatzimanikatis at EPFL and Professor Dominique Soldati-Favre at the University of Geneva. Together, they formed the "MalarX" consortium, which is sponsored by the Swiss National Science Foundation.

Hatzimanikatis’s group, led by computer modeling expert Anush Chiappino-Pepe, created models that show essential metabolic pathways of the Plasmodium parasite. "Thanks to these models, it is now possible to predict which of the previously unexplored genes are vital for the parasite, and are therefore suitable targets for malaria control,” says Chiappino-Pepe, who is now at Harvard Medical School.

Some of the predictions were then experimentally confirmed by the Bern researchers in collaboration with the group of Professor Chris Janse at the University of Leiden. “The genome-wide screen, with the corresponding metabolic models represents a breakthrough in malaria research," says Magali Roques at the Bern team.

“Our results will support many malaria researchers worldwide,” adds Ellen Bushell, a former scientist at the Sanger Institute who also contributed to the research. “They can now concentrate on essential parasite genes and thus develop efficient drugs and vaccines against various stages of the parasite's life.”

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