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NEWS New research into the different life stages of malaria parasites has identified promising areas for new drug targets aimed at disrupting the parasite’s growth in the liver. Scientists from Umeå University played an important part in a collaborative project which discovered seven metabolic pathways that the parasite needs to infect the liver, where the parasite multiplies rapidly before invading the blood and causing malaria.
The study, published today in Cell, is the first systematic study of gene function in the liver form of Plasmodium malaria parasites. By ‘deleting’ certain genes from the parasite’s DNA and observing the effect on its behaviour, the team were able to identify which ones are essential for the liver stage of its lifecycle. This information will help to develop drugs that target these genes and interrupt the parasite’s ability to cause malaria.
Malaria remains a major global health problem. Between 2000 and 2015, an ongoing drive to eliminate the disease has seen worldwide malaria deaths halve from 864,000 to 429,000 per year. But the increase in drug-resistant strains of malaria means this progress may be at risk if new forms of treatment are not developed.
The various species of Plasmodium parasite have complex lifecycles that begin in mosquitos before continuing in mammalian hosts, such as humans or rodents. Around 100 parasites transfer to the mammal host through a mosquito bite, where they then move to the liver, a metabolically rich environment that acts as an incubator for them to reproduce rapidly. After 7-10 days, around 10,000 parasites leave the liver to invade red blood cells, where they cause the symptoms of malaria.
In the new study, researchers used a new genetic technology they developed to carry out a genome-wide gene deletion study on the parasite Plasmodium berghei, which infects certain species of rodent. The data were generated using a malaria mouse model available at the Institute of Cell Biology at the University of Bern.
More than a thousand parasite genes were switched off, or ‘knocked out’. The team then used next generation genome sequencing technology at the Wellcome Sanger Institute to analyse how the removal of individual genes affected the parasite’s lifecycle.
The team found 461 genes that are essential for efficient parasite transmission to mosquitoes and through the liver stage back into the bloodstream of mice. From this data, a model of P. berghei liver-stage metabolism was created by scientists in Lausanne that allowed the researchers to pinpoint seven metabolic pathways essential to the parasite’s ability to grow rapidly in the liver.
"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," Dr Ellen Bushell from Umeå University says.
Most anti-malarial drugs target the blood stage of the parasite’s lifecycle, but very few target the liver stage. Growing resistance to blood-stage malaria drugs, such as artemisinin, makes the possibility of new liver-stage drugs increasingly important.
A further benefit to drugs that target Plasmodium parasites in the liver would be their effectiveness against forms of malaria, such as Plasmodium vivax, that can lay dormant in the liver and cause recurrence of symptoms for years after the initial infection.
“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 stages parasites are an important reservoir of infection, but there are far fewer of them, which makes the development of resistance at this stage less likely. The discovery of new liver-stage drug targets is therefore both timely and important,” Professor Oliver Billker, from Umeå University says.
Dr Bushell and Professor Billker have recently started research groups at Umeå University, where they are using the powerful genetic tools they developed at the Wellcome Sanger Institute in Cambridge for research into malaria parasites and how they cause disease.
Rebecca R. Stanway et al. (2019): Genome Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage. Cell. DOI:https://doi.org/10.1016/j.cell.2019.10.030