Putting the brakes on malaria

U. NOTTINGHAM (UK) — More than a third of the 72 molecular switches that control key stages in the life cycle of the malaria parasite can be disrupted in some way.

The finding is a significant breakthrough in the search for inexpensive, effective vaccines and drugs to stop the transmission of a disease that kills up to a million children a year, according to new research.

Until now little has been known about the cellular processes involved in the development of this deadly disease.

The research, published in the journal Cell Host & Microbe, involved the first comprehensive functional analysis of protein kinases in any malaria parasite.

It is also the largest gene knock-out study in Plasmodium berghei—a malaria parasite infecting rodents.

“Blocking parasite transmission is recognized as an important element in the global fight to control malaria,” says Rita Tewari, in the school of biology at the University of Nottingham.

“Kinases are a family of proteins which contribute to the control of nearly all cellular processes and have already become major drug targets in the fight against cancer and other diseases.

“Now we have identified some key regulators that control the
transmission of the malaria parasite. Work to develop drugs to eradicate this terrible disease can now focus on the best targets. This study shows how systematic functional studies not only increase our knowledge in understanding complexity of malaria parasite development but also gives us the rational approach towards drug development.”

The life cycle of the malaria parasite is complex. Once the mosquito has feasted off infected blood, fertilization takes place within the mosquito. The deadly parasites are then injected back into another host in large numbers when the mosquito bites again.

Once inside its mammalian host the parasite first infects the liver where it replicates again. After 48 hours millions of parasites are released into the red bloods cells of its host where they attack in vast numbers overwhelming their host producing high fever and sickness.

“This is a major leap forward,” says Oliver Billker, an expert in pathogen genetics at the Wellcome Trust Sanger Institute.

“We can now set aside these 23 functionally redundant genes. This act of prioritization alone has narrowed the set of targets for drug searches by a third.

“Our study demonstrates how a large scale gene knockout study can guide drug development efforts towards the right targets. We must now develop the technology to ask across the genome which pathways are important for parasite development and transmission.”

As the malaria parasite becomes increasingly resistant to existing drugs and vaccines the race to find ways of blocking the transmission of malaria is becoming increasingly important.

Last month the journal PLoS One published Tewari’s research which identified a protein, PF16, critical in the development of the malaria parasite — specifically the male sex cells (gametes) — which are essential in the spread by mosquitoes of this lethal parasite. The study found a way of disabling the PF16 protein.

In future studies, Tewari’s group will concentrate on the role of other signaling molecules like phosphatases, kinases and armadillo repeat proteins and their interaction in understanding malaria parasite development with the aim to identify the best drug or vaccine target along the way.

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