Study highlights role of jaundice-associated pigment in protecting against malaria

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Scientists say they have new experimental evidence of a novel role for bilirubin, a natural yellow pigment found in the body, in protecting humans from the worst effects of malaria and potentially other infectious diseases. Findings could advance the search for drugs that mimic the pigment bilirubin, or deliver it to the body to help protect people from severe forms of some infections. Bilirubin is also thought to play an important role in protecting the brain from neurodegenerative disease. New research suggests that a pigment that causes yellowing of the skin, or jaundice, may help protect people from the most severe consequences of malaria. The report, which builds on a previous Johns Hopkins Medicine study on the protective role of bilirubin in the brain, is a collaboration between the labs of Miguel Soares, Ph.D., at the Gulbenkian Institute for Molecular Medicine in Portugal, and Bindu Paul, Ph.D., at Johns Hopkins Medicine.

The parasitic disease, transmitted by the bites of some mosquitoes, is estimated to affect more than 260 million people a year in tropical and subtropical areas, and kills around 600,000 people annually, according to the World Health Organization.

The new research findings suggest bilirubin may be a potential target of drugs that boost its production to prevent malaria’s most deadly or debilitating effects, says Paul, associate professor of pharmacology and molecular sciences at the Johns Hopkins University School of Medicine. Although bilirubin is one of the most commonly measured metabolites in the blood, Paul says its roles in the body are only beginning to be understood.

Additionally, doctoral student Ana Figueiredo, of the Soares lab, who helped spearhead the study, says these findings may indicate that bilirubin could help protect people against other infectious diseases.

A report on the findings was published June 12 in the journal Science.

Soares connected with Paul after seeing her National Institutes of Health-funded research published in Cell Chemical Biology in 2019, which identified the important role bilirubin plays in protecting brain cells from damage from oxidative stress. Although prior research from the Soares lab had shown protective effects potentially related to bilirubin in people with malaria, Paul says it was unclear whether the pigment protected or worsened the disease.

The mouse model and methods used to measure bilirubin in the new study were initially developed by Paul’s lab for her 2019 study.

Jaundice, or yellowing of the skin, is a common presentation of malaria, says Paul, and anywhere from 2.5% to 50% of patients with malaria experience jaundice, according to two studies published in the New England Journal of Medicine and Clinical Infectious Disease.

In a bid to pin down the role of bilirubin, the scientists collaborated with the lab of Florian Kurth at Charité Berlin, Germany, and Centre de Recherches Médicales de Lambaréné in Gabon to conduct an analysis of blood samples taken with permission from a volunteer group of 42 patients who were infected with malaria parasite P. falciparum, which causes the deadliest form of the condition, according to the World Health Organization.

 Using techniques developed by Paul and further optimized at the Gulbenkian Institute to measure bilirubin and its precursor biliverdin, the scientists measured the amount of bilirubin not yet processed by the liver in blood samples with both asymptomatic and symptomatic malaria. They found that, on average, people with asymptomatic malaria had 10 times more unprocessed bilirubin in the blood as symptomatic people, and suspected that accumulation of the pigment may have helped protect them from malaria.

Next, the researchers exposed normal mice and mice genetically engineered to lack BVRA, a protein that helps produce bilirubin, to a form of malaria that infects rodents.

Using the same methods developed by Paul, the researchers analyzed the rate at which the malaria parasite died off in both bilirubin-lacking mice and in normal mice. 

In normal mice, Soares says the concentration of unprocessed bilirubin in their systems increased significantly after they were infected with malaria, and all of the mice survived. In the mice lacking BVRA, the parasite spread vigorously, and all of the mice died.

The scientists at the Gulbenkian Institute then set out to test whether bilirubin could help BVRA-lacking mice overcome their infections, or whether it contributed to worsening symptoms. They gave bilirubin to malaria-infected mice that were also lacking BVRA, and saw that providing mice with higher doses of bilirubin resulted in survival times similar to that of normal mice.

Paul plans to further study bilirubin in mice to determine the potential protective effect of the pigment in the brain.

“Bilirubin was once considered to be a waste product,” Paul says. “This study affirms that it could be one critical protective measure against infectious disease, and potentially neurodegenerative diseases.”

Funding support for this research was provided by Fundação para a Ciência e Tecnologia Portugal, the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie, the DFG Cluster of Excellence, the Gulbenkian Foundation, the la Caixa Foundation, the Human Frontier Science Program, the Lise Meitner Excellence Programme of the Max Planck Society, the European Molecular Biology Organization, the European Union’s Horizon 2020 research and innovation programme, the Academy of Finland, the Sigrid Juselius Foundation, Biocenter Finland, ELIXIR Finland, the American Heart Association/Paul Allen Frontiers Group, the National Institutes of Health National Institute on Aging (1R21AG073684-01 and R01AG071512), the Johns Hopkins Catalyst Award, U.S. Public Health Service, European Research Council, Oeiras-ERC Frontier Research Incentive Awards and SymbNET Research Grants.

In addition to Paul, Soares and Figueiredo, other scientists who contributed to this research are Chirag Vasavda (a Johns Hopkins M.D./Ph.D. at the time of the study) of Johns Hopkins; Sonia Trikha Rastogi, Susana Ramos, Elisa Jentho, Elisa Jentho, Sara Pagnotta, Miguel Mesquita, Silvia Cardoso, Erin M. Tranfield, Ana Laura Sousa, Jamil Kitoko, Sara Violante, Tiago Paixão and Rui Martins from the Gulbenkian Institute for Molecular Medicine; Fátima Nogueira and Denise Duarte from Universidade NOVA de Lisboa, Portugal; Katherine De Villiers from Stellenbosch University, South Africa; António G. Gonçalves de Sousa, Sini Junttila and Laura L. Elo from University of Turku and Åbo Akademi Universit, Finland; Lasse Votborg-Novél and Silvia Portugal from Max Planck Institute for Infection Biology, Germany; Cäcilie von Wedel, Pinkus Tober-Lau, Silvia Portugal and Florian Kurth from Charité Universitätsmedizin Berlin, Germany; Giulia Bortolussi and Andrés F. Muro from International Centre for Genetic Engineering and Biotechnology Padriciano, Italy; Jessica Thibaud from Stellenbosch University, South Africa; Sandra N. Pinto from Instituto Superior Técnico, Portugal; Ghyslain Mombo-Ngoma and Johannes Mischlinger from Centre de Recherches Médicales de Lambaréné, Gabon; Marta Alenquer and Maria João Amorim from Universidade Católica Portuguesa, Portugal; Piter J. Bosma from University of Amsterdam, the Netherlands, Bernhard Drotleff from Metabolomics Core Facility, Germany.

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