Updates

Researchers from the Turku Bioscience Centre at the University of Turku in Finland collaborated with a leading malaria research group at Gulbenkian Institute of Molecular Medicine (GIMM) in Portugal to elucidate a metabolite-based defense mechanism against malaria severity.

Following infection with Plasmodium falciparum, the most common malaria-causing parasite species, some patients may develop a more severe form of disease characterized by yellowing of the skin and sclera – a condition known as jaundice. Jaundice results from the accumulation of the yellow pigment bilirubin, traditionally thought to be a “waste product” of the infection. For the first time, researchers provide evidence that the accumulation of unconjugated bilirubin in the plasma represents an adaptive defense mechanism, rather than a maladaptive response, to Plasmodium species infection. The findings suggest that the accumulation of unconjugated bilirubin in plasma is a protective metabolic response to Plasmodium spp. infection that limits the severity of malaria. The mechanism resembles the action of the anti-malarial agent chloroquine, although it is less potent, opening a new avenue to explore this natural host defense response as a potential therapeutic approach to malaria. The study, published in the prestigious journal Science, was led by Dr. Miguel Soares’s laboratory at the GIMM in Portugal, with supporting contributions to the single-cell data analysis from Prof. Laura Elo’s laboratory at the Turku Bioscience Centre, University of Turku, in Finland.

Single-cell gene expression analysis of Plasmodium parasites in a mouse model lacking the bilirubin-processing enzyme reveals metabolic and life-cycle changes

Prof. Laura Elo’s team analyzed single-cell gene expression data from Plasmodium-infected red blood cells isolated from control mice and from a bilirubin-deficient mouse model. “Analyzing single-cell gene expression profiles from Plasmodium-infected red blood cells presents unique challenges compared to human single-cell data,” explain A/Prof. Sini Junttila and PhD student António Sousa. “A key difficulty is determining whether differences in gene expression profiles reflect true variations in the parasite’s life-cycle stages or are due to technical artifacts. Another challenge is identifying the most effective way to integrate gene expression data from Plasmodium cells isolated from control and bilirubin-deficient mice.”

The results showed more Plasmodium parasite cells at an early stage of development (early trophozoites) in mice lacking the ability to process bilirubin, suggesting that bilirubin helps arrest the parasite’s development. “This collaboration allowed us to dissect, at single-cell resolution, how bilirubin impacts Plasmodium biology,” says Prof. Laura Elo.

“The high-end expertise and the collegial interaction provided by the Elo laboratory were a stepping stone in the identification of how bilirubin modulates the gene expression profile of Plasmodium to reduce its virulence,” says Dr. Miguel Soares.

Further experiments led by Dr. Miguel Soares’s team at GIMM showed that unconjugated bilirubin impairs the malaria parasite’s proliferation by disrupting the function of its mitochondria, the “powerhouses” of cells responsible for producing energy. This interference reduces the parasite’s ability to generate energy through glycolysis and to produce essential building blocks like pyrimidines. While these effects contributed to reduced parasite fitness, they were not sufficient to fully explain the anti-malarial impact observed. Building on this, researchers discovered that unconjugated bilirubin also disrupts the formation of hemozoin, a crystal that the parasite creates inside its food vacuole to safely store free heme, a toxic byproduct of digesting red blood cell hemoglobin. By blocking hemozoin formation, bilirubin causes toxic substances like free heme to accumulate, which ultimately harms the parasite and reduces its survival.

In conclusion, the induction of bilirubin production in response to Plasmodium spp. infection is a metabolite-based resistance mechanism against malaria. We speculate that while evolutionary conserved, this defense strategy carries as an evolutionary trade-off, the insidious prevalence of neonatal jaundice, which can lead to encephalopathy. Considering the extraordinary selective pressure exerted by malaria on human population, it is conceivable that the anti-malarial effects of unconjugated bilirubin outcompeted the fitness costs associated with high incidence neonatal jaundice in populations originating in endemic areas of malaria.

* Figueiredo A, Rastogi ST, Ramos S, Nogueira F, De Villiers K, Gonçalves de Sousa AG, Votborg-Novél L, von Wedel C, Tober-Lau P, Jentho E, Pagnotta S, Mesquita M, Cardoso S, Bortolussi G, Muro AF, Tranfield EM, Thibaud J, Duarte D, Sousa AL, Pinto SN, Kitoko J, Mombo-Ngoma G, Mischlinger J, Junttila S, Alenquer M, Amorim MJ, Vasavda C, Bosma PJ, Violante S, Drotleff B, Paixão T, Portugal S, Kurth F, Elo LL, Paul BD, Martins R, Soares MP (2025) A metabolite-based resistance mechanism against malaria. Science. DOI: 10.1126/science.adq6741

>>Original article

>>Read the press release in Finnish