A metabolite-based resistance mechanism against malaria
Jaundice is a common presentation of <i>Plasmodium</i> <i>falciparum</i> malaria, which arises from the accumulation of circulating bilirubin. It is not understood whether it represents an adaptive or maladaptive response to <i>Plasmodium</i> spp. infection. We found that asymptomatic <i>P. falciparum</i> infection in humans was associated with a higher ratio of unconjugated over conjugated bilirubin and parasite burden compared with symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, through genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1), was protective against malaria in mice. Unconjugated bilirubin inhibited <i>P. falciparum</i> proliferation in red blood cells by a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin crystallization and compromised the parasite's food vacuole. Hence, jaundice appears to represent a metabolic response to <i>Plasmodium</i> spp. infection that limits malaria severity.
Authors
- Bindu D. Paul (ORCID: https://orcid.org/0000-0002-1862-6103)
- Chirag Vasavda (ORCID: https://orcid.org/0000-0003-4558-4698)
- Katherine A. de Villiers (ORCID: https://orcid.org/0000-0002-2932-395X)
- Miguel Mesquita (ORCID: https://orcid.org/0000-0001-5927-790X)
- Ghyslain Mombo‐Ngoma (ORCID: https://orcid.org/0000-0003-2658-8706)
- Sílvia Portugal (ORCID: https://orcid.org/0000-0003-4567-9101)
- Sílvia Cardoso (ORCID: https://orcid.org/0000-0003-4639-698X)
- Andrés Fernando Muro (ORCID: https://orcid.org/0000-0002-9628-0494)
- Sara Pagnotta (ORCID: https://orcid.org/0000-0002-0931-8942)
- Sara Violante (ORCID: https://orcid.org/0000-0003-2124-5712)
- Sandra N. Pinto (ORCID: https://orcid.org/0000-0002-3205-9459)
- Erin M. Tranfield (ORCID: https://orcid.org/0000-0002-1542-7459)
- Tiago Paixão (ORCID: https://orcid.org/0000-0003-2361-3953)
- Elisa Jentho (ORCID: https://orcid.org/0000-0002-4790-7860)
- Ana Laura Sousa (ORCID: https://orcid.org/0000-0001-6067-8794)
- Denise Duarte (ORCID: https://orcid.org/0000-0002-6853-7598)
- Rui Martins (ORCID: https://orcid.org/0000-0001-8106-6324)
- Piter J. Bosma (ORCID: https://orcid.org/0000-0001-8302-1672)
- Fátima Nogueira (ORCID: https://orcid.org/0000-0003-0313-0778)
- Laura L. Elo (ORCID: https://orcid.org/0000-0001-5648-4532)
- Jamil Z. Kitoko (ORCID: https://orcid.org/0000-0003-0973-5460)
- Maria João Amorim (ORCID: https://orcid.org/0000-0002-4129-6659)
- Giulia Bortolussi (ORCID: https://orcid.org/0000-0001-9470-0902)
- Miguel P. Soares (ORCID: https://orcid.org/0000-0002-9314-4833)
- Pinkus Tober‐Lau (ORCID: https://orcid.org/0000-0002-9148-3663)
- Johannes Mischlinger (ORCID: https://orcid.org/0000-0002-2012-6327)
- Bernhard Drotleff (ORCID: https://orcid.org/0000-0003-0914-6578)
- Sini Junttila (ORCID: https://orcid.org/0000-0003-3754-5584)
- Florian Kurth (ORCID: https://orcid.org/0000-0002-3807-473X)
- António G. G. Sousa (ORCID: https://orcid.org/0000-0003-4779-6459)
- Marta Alenquer (ORCID: https://orcid.org/0000-0003-3062-1222)
- Susana Ramos (ORCID: https://orcid.org/0000-0001-6356-1065)
- Lasse Votborg-Novél (ORCID: https://orcid.org/0000-0003-0381-0669)
- Ana Figueiredo (ORCID: https://orcid.org/0000-0001-9075-2238)
- Sharad Rastogi (ORCID: https://orcid.org/0000-0002-2333-7170)
- Cäcilie von Wedel
- Jessica Thibaud (ORCID: https://orcid.org/0000-0001-5917-3852)
Institutions
- Åbo Akademi University (FI)
- Johns Hopkins University (US)
- University of Turku (FI)
- Universität Hamburg (DE)
- Turku Centre for Computer Science (FI)
- Universidade Católica Portuguesa (PT)
- Stellenbosch University (ZA)
- Johns Hopkins Medicine (US)
- Humboldt-Universität zu Berlin (DE)
- Max Planck Institute for Infection Biology (DE)
- Centre de Recherche Médicales de Lambaréné (GA)
- Instituto de Medicina Tropical (PY)
- Hospital de Egas Moniz (PT)
- University Medical Center Hamburg-Eppendorf (DE)
- Jena University Hospital (DE)
- European Molecular Biology Laboratory (DE)
- Lieber Institute for Brain Development (US)
- Instituto de Investigação Científica Tropical (PT)
- Institute for Biotechnology and Bioengineering (PT)
- Instituto Gulbenkian de Ciência (PT)
- Friedrich Schiller University Jena (DE)
- Universidade Nova de Lisboa (PT)
- University of Amsterdam (NL)
- International Centre for Genetic Engineering and Biotechnology (IT)
- Bernhard Nocht Institute for Tropical Medicine (DE)
Publication Details
- Journal
- Science
- Published
- 2025-06-12
- DOI
- https://doi.org/10.1126/science.adq6741
- Citations
- 7
- Primary Topic
- Neonatal Health and Biochemistry
- Type
- article
- Field-Weighted Citation Impact
- 24.46