Despite great efforts in medicine and science, more than 400,000 people worldwide are still dying of malaria. The infectious disease is transmitted by the bite of mosquitoes infected with the malaria parasite Plasmodium. The genome of the parasite is relatively small with about 5,000 genes. In contrast to human cells, Plasmodium parasites only have a single copy of each individual gene. If one removes a gene from the entire genome of the parasite, this leads therefore directly to a change in the phenotype of the parasite.
An international consortium has taken advantage of this fact. The researchers have carried out a genome-wide gene deletion study on malaria parasites: They specifically removed over 1300 individual genes, observed the effects during the entire life cycle of the parasite and were thus able to identify many new targets in the pathogen. The present study was published in the prestigious journal Cell.
The researchers used a malaria mouse model. Each of the 1300 parasite genes was replaced by an individual genetic code to analyze how the removal of the individual genes affects the parasite. The use of individual codes allows to study many parasites simultaneously and thus drastically shortens the time of their analysis. After three years of research, the international consortium succeeded in systematically screening the genome of the parasite in all life cycle stages. "The deletion screen enabled us to identify hundreds of targets, particularly in the parasite's metabolism," said one of the lead authors of this study.
Using data of the malaria genome screen, the group has calculated models that show essential metabolic pathways of the 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" adds model expert.
The researchers identify seven metabolic subsystems that become essential at the liver stages compared with asexual blood stages: type II fatty acid synthesis and elongation (FAE), tricarboxylic acid, amino sugar, heme, lipoate, and shikimate metabolism. Selected predictions from the model are individually validated in single mutants to provide future targets for drug development.
Some of these predictions were then experimentally confirmed by the researchers. "The genome-wide screen with the corresponding metabolic models represents a breakthrough in malaria research," said another author. "Our results will support many malaria researchers worldwide. They can now concentrate on essential parasite genes and thus develop efficient drugs and vaccines against various stages of the parasite's life" added another author.
Genetic screening of malaria parasite depicts metabolic vulnerability
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