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Malaria drug target stops parasite entering liver

Friday November 15th, 2019

New drug targets that aim to stop malaria parasites entering the liver have been identified in the first study of its kind, it was announced yesterday.

Scientists from the Wellcome Sanger Institute, the University of Bern, Switzerland, and Umeå University, Sweden, say they hope their findings will lead to new treatment options.

In what is the first systematic study of gene function in the Plasmodium malaria parasite family, the team discovered seven metabolic pathways that the parasite needs to infect the liver.

They deleted specific genes from the parasite’s DNA and observed the effect on its behaviour to identify which ones are essential for the liver stage of its life cycle.

They say this information will help to develop drugs that target these genes and interrupt the parasite’s ability to cause malaria.

The various species of Plasmodium parasite have complex life cycles that begin in mosquitoes before continuing in mammalian hosts. About 100 parasites transfer to the mammal host through a mosquito bite, where they then move to the liver, which acts as an incubator for them to reproduce rapidly.

After seven to ten days, about 10,000 parasites leave the liver to invade red blood cells, where they cause the symptoms of malaria.

In the new study, published in Cell, researchers carried out a genome-wide gene deletion study Plasmodium berghei, switching off more than 1000 parasite genes. Each gene was assigned a unique DNA barcode.

Using next-generation genome sequencing technology, the team counted the barcodes to analyse how the removal of individual genes affected the parasite’s life cycle.

They found 461 genes that are essential for efficient parasite transmission to mosquitoes and through the liver stage back into the bloodstream of mice, which enabled them to create a model of P. berghei liver-stage metabolism that highlighted seven essential metabolic pathways for the parasite to grow in the liver.

Dr Ellen Bushell, from Umeå University, 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."

Few anti-malarial drugs target the target the liver stage of the parasite’s life cycle. The team say another benefit of having drugs target Plasmodium parasites in the liver is their effectiveness against forms of malaria, such as Plasmodium vivax.

Rebecca R. Stanway et al. Genome Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage. Cell 14 November 2019; doi: 10.1016/j.cell.2019.10.030

Tags: Africa | Europe | Genetics | Pharmaceuticals

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