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Gene Screen Leads to Potential Malaria Targets in Liver-Stage Plasmodium Parasites

NEW YORK – A team from Europe has uncovered a handful of metabolic processes that appear to be essential for Plasmodium parasites during a relatively unstudied liver stage of infection.

Researchers at the University of Bern, Wellcome Sanger Institute, Umeå University, and elsewhere turned to genomic, transcriptomic, and metabolomic approaches — in combination with a gene knockout screen — to define key genes and pathways in P. berghei across the parasite's life cycle.

In addition to finding hundreds of essential genes in mosquito, liver, and bloodstream stages of infection, the team's analyses highlighted seven metabolic pathways that appear especially important for the parasite while it ramps up its growth in the liver before transitioning to an infected host's blood. The findings appeared online today in an open access Cell paper.

"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," co-first author Ellen Bushell, a researcher affiliated with Umeå University and the Sanger Institute, said in a statement.

Malaria-causing Plasmodium parasites, in sporozoite form, move from Anopheles mosquito vectors into liver hepatocyte cells of infected host animals, where they multiply quickly for a few days before moving into the bloodstream, shifting between sexual reproduction in the mosquito and asexual replication in blood erythrocyte cells.

"With this immense and rapid expansion [in the liver]," the authors explained, "parasites need to be highly metabolically active, despite their dependence on the host cell for nutrient acquisition."

In an effort to find treatment targets beyond the blood stages of malaria infection, where Plasmodium has found ways to dodge many available drugs, the researchers tapped into a collection of barcoded P. berghei parasites, each missing a different gene, selecting 1,342 barcoded mutants capable of surviving during the blood stage of infection despite the missing genes.

The team followed the phenotypes of these parasites across the Plasmodium life cycle, and used barcode sequencing for a "mosquito-stage liver-stage" screen to quantify the relative abundance of different mutant parasites in the mosquito midgut, salivary gland, and mouse host, pooling 60 mutant parasites in each experiment.

The search led to 461 essential genes during the mosquito, liver, or blood stages of infection. By folding in additional transcriptomic data generated for Plasmodium parasite-infected liver samples and insights from a PhenoMapping computational framework, the team came up with a liver metabolic model known as iPbe-liver.

"We used this model to examine the reasons underlying the observed loss-of-function phenotypes and provide new insights into liver-stage physiology, systematically predicting thermodynamic bottlenecks, genetic interactions, and growth-limiting nutrients," the authors explained.

Those analyses pointed to the importance of amino sugar, tricarboxylic acid, heme, and other metabolic subsystems that appear to be crucial for liver-stage P. berghei parasites — findings the team shored up with follow-up experiments on 20 more mutant parasites, each missing a different gene of interest.

"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," co-senior author Oliver Billker, a researcher affiliated with the Sanger Institute and Umeå University, said in a statement. "The discovery of new liver-stage drug targets is therefore both timely and important."

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