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Targets for new malaria drugs found by scientists at Wellcome Sanger Institute, the University of Bern and Umeå University




New targets for drugs that could stop the malaria parasite in its tracks have been identified.

Scientists at the Wellcome Sanger Institute in Hinxton, the University of Bern in Germany and Umeå University in Sweden collaborated on a study that found seven metabolic pathways used by the parasite when infecting the liver.

Malaria kills hundreds of thousands of people every year
Malaria kills hundreds of thousands of people every year

It is in this organ that the parasite multiplies at pace before invading the blood, causing malaria.

Dr Ellen Bushell, from Umeå University and an alumnus of the Wellcome Sanger Institute, said: "To identify seven metabolic pathways that are essential to a Plasmodium parasite’s ability to reproduce in the host liver is incredibly exciting. Our findings will allow malaria researchers worldwide to focus on these essential genes, in order to develop efficient drugs and vaccines to help tackle malaria."

Despite a major effort to tackle the disease, malaria remains a huge global health problem.

Worldwide deaths halved between 2000 and 2015 from 864,000 to 429,000 per year, but this progress is at risk because of the development of drug-resistant strains of malaria, which is spread by mosquitoes infected with parasites.

A mosquito sucking blood. (21666296)
A mosquito sucking blood. (21666296)

The new study, published in Cell, is the first to systematically examine gene function in the Plasmodium malaria parasite family.

By observing the impact of deleting certain genes from the parasite’s DNA, the researchers identifies those essential for the liver stage of its life cycle.

Dr Oliver Billker, from Umeå University and an alumnus of the Wellcome Sanger Institute, said: “The world has achieved great success in fighting malaria by targeting the blood stage of Plasmodium parasites, halving the number of malaria deaths in less than two decades. But Plasmodium parasites have repeatedly and rapidly developed resistance to all available blood-stage drugs.

“Liver-stage parasites are an important reservoir of infection, but because there are far fewer of them it makes the development of drug resistance at this stage less likely. The discovery of new liver-stage drug targets is therefore both timely and important.”

The malaria transmission cycle. (21666289)
The malaria transmission cycle. (21666289)

The Plasmodium parasite - of which there are several species - have complex life cycles.

A bite from an infected mosquito can transfer about 100 parasites to a mammal, such as a human or rodent.

They move to the liver, which is a metabolically rich environment and acts as an incubator.

After seven to 10 days, about 10,000 parasites leave the liver and invade red blood cells, leading to malaria symptoms.

The genome-wide gene deletion study was carried out on the parasite Plasmodium berghei, which infects certain species of rodent.

A malaria mouse model from the Institute of Cell Biology at the University of Bern was used by the researchers, who switched off - or ‘knocked out’ - more than 1,000 parasite gene.

Each gene was assigned a unique DNA barcode. Using next generation genome sequencing technology at the Wellcome Sanger Institute, these barcodes were counted and analysis carried out to show how the removal of individuals genes impacted on the parasite’s life cycle.

The symptoms of malaria. (21666293)
The symptoms of malaria. (21666293)

Some 461 genes were found to be essential for the effective transmission of the parasite to mosquitoes, on through the liver stage and back into the bloodstream of mice.

Using this data, scientists in Lausanne created a model of P. berghei liver-stage metabolism, enabling them to determine the seven metabolic pathways used by the parasite to grow at pace in the liver.

The growing resistance to blood-stage malaria drugs like artemisinin has brought the need for liver-stage drugs into sharp focus.

But targeting this stage would have a further benefit, as the drugs would be effective against forms of malaria like Plasmodium vivax, which can lay dormant in the liver and cause recurring symptoms for years after the initial infection.

A map of countries affected by malaria, as of March 2015, Image: Petaholmes.. (21666283)
A map of countries affected by malaria, as of March 2015, Image: Petaholmes.. (21666283)

The work required both world-leading sequencing and cloning capabilities at the Wellcome Sanger Institute and the excellent technology available at the Institute of Cell Biology in Bern, where the parasite’s life cycle was established.

Professor Volker Heussler, from the Institute of Cell Biology, said: “Twenty-two international scientists from the fields of molecular biology, parasitology, statistics and mathematical modelling participated in this project. This illustrates the effort in conducting this study, analysing the data and modelling the experimental findings to bring them into a meaningful context.”

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