Abstract
Jaundice is a common presentation of Plasmodium falciparum malaria, which arises from the accumulation of circulating bilirubin. It is not understood whether it represents an adaptive or maladaptive response to Plasmodium spp. infection. We found that asymptomatic P. falciparum 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 P. falciparum 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 Plasmodium spp. infection that limits malaria severity.
| Original language | English |
|---|---|
| Article number | adq6741 |
| Journal | Science |
| Volume | 388 |
| Issue number | 6752 |
| DOIs | |
| Publication status | Published - 12 Jun 2025 |
| MoE publication type | A1 Journal article-refereed |
Funding
We thank all members of the Inflammation Laboratory at GIMM for insightful technical and intellectual contributions, GIMM flow cytometry, and use of the animal facility. We thank D. R. de Waart (University of Amsterdam) for quantification of unconjugated bilirubin by high-performance liquid chromatography (not shown); A.Vaidya (Drexel University) for kindly providing the PfD10 and PfD10TgDHODH strains and for insightful advice; the Centre de Recherches Médicales de Lambaréné for support of the DEMIT study; L. Bardtke, P. Kroneberg, A. K. Kneller, N. Schirra,J. L. Schöllgen, and C. Conrad for sample and data processing at Charité – Universitätsmedizin Berlin; O. Chertkov (Católica Biomedical Research Centre, Portugal); the Protein Purification Research Facility and the Bacterial Imaging Cluster at ITQB NOVA for support for protein purification and quantification; and A. Malheiro (Advanced Electron Microscopy, Imaging and Spectroscopy – AEMIS) for use of the INL User Facilities. Funding: This work was supported by Fundação para a Ciência e Tecnologia (2020.04797.BD and COVID/BD/153665/2024 to A.F.; GHTMUID/04413/2020, LA-REAL-LA/P/0117/2020, and 2022.02426.PTDC to F.N.; FEDER/29411/2017 to S.R.; 2020.04797.BD to D.D.; UIDB/04565/2020, LA/P/0140/2020, and 2022.03627.PTDC to S.P.; 2022.08590.PTDC_ EXPL (DOI 10.54499/2022.08590.PTDC) to J.K.; 2021.03494.CEECIND (DOI10.54499/2021. 03494.CEECIND/CP1674/CT0004) to R.M.; 2023.09168.CEECID to E.J.; and FEDER/29411/ 2017, PTDC/MED-FSL/4681/2020 (DOI 10.54499/PTDC/MED-FSL/4681/2020), 2022.02426.PTDC (DOI 10.54499/2022.02426.PTDC), and Congento LISBOA-01-0145-FEDER-022170 to M.P.S.This work was also supported by European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie (955321 to A.G.G.S., 753236 to R.M.); DFG Cluster of Excellence “Balance of the Microverse”EXC 2051; 390713860 (E.J., M.P.S. as associated member); DFG IRTG 2290 “Molecular interactions in malaria” (P.T.-L., F.K., and the DEMIT study); Gulbenkian Foundation (S.R., M.P.S., and I.B.B. 2021-51/ BI-D/2021 to S.T.); la Caixa Foundation HR18-00502 (E.J.,J.K., M.P.S.); Human Frontier Science Program (LT0043/2022-L to J.K.); Lise Meitner Excellence Programme of the Max Planck Society (S.P.); European Molecular Biology Organization (EMBO Long-term Fellowship ALTF290-2017 to R.M.); European Union’s Horizon 2020 research and innovation programme (grant 955321); Academy of Finland (grant 329278 to L.L.E.); Sigrid Juselius Foundation (L.L.E.); Biocenter Finland (L.L.E.); ELIXIR Finland (L.L.E.); American Heart Association/Paul Allen Frontiers Group (project 19PABH134580006 to B.D.P.); NIH/NIA (B.D.P. by 1R21AG073684-01 and R01AG071512); The Johns Hopkins Catalyst Award (B.D.P.); Solve ME/ CFS Initiative (grant 90089823 to B.D.P.); US Public Health Service (grant DA044123 to B.D.P.); European Research Council (grant 101001521 to M.J.A.); Oeiras-ERC Frontier Research Incentive Awards (M.P.S.); and H2020-WIDESPREAD-2020-5-952537 SymbNET Research Grants (M.P.S.). Author contributions: Conceptualization: M.P.S.,A.F., R.M., K.D.V., S.Po.; Data curation: A.G.G.d.S., S.J., L.V.-N., C.v.W., P.T.-L., F.K., S.V.,T.P., B.D. ; Formal analysis: A.G.G.d.S., S.J., L.V.-N., C.v.W., P.T.-L., F.K., S.V.,T.P., B.D. ; Resources: G.M.-N.,J.M., C.v.W., P.T.-L., F.K., B.D.P., M.J.A., G.B.,A.F.M.; Investigation: A.F., S.R., E.J.,J.T., D.D.,A.L.S., S.Po., S.Pa., S.T.R., M.M., S.C., M.A.,J.K., G.M.-N.,J.M., C.v.W., P.T.-L., F.K., M.A., C.V., R.M.; Visualization: A.F., R.M., M.P.S.; Funding acquisition: M.P.S., R.M., F.K.; Project administration: M.P.S., R.M.; Supervision: M.P.S., R.M., F.N., S.J., L.L.E., S.N.P., S.Po.,J.K., P.J.B., F.K., E.M.T., K.D.V.; Writing – original draft: M.P.S.; Writing – review & editing: M.P.S.,A.F., R.M., S.T.R., S.R. Competing interests: The authors declare that they have no competing interests. C.V. is an inventor on US patent US11442059 held by The Johns Hopkins University, which covers a method for treating a chronic itch condition by administering small-molecule MrgprX4 antagonists, and on US patent application no. 18/726,735 submitted by The Johns Hopkins University, which covers treatment and prevention of trigeminal neuralgia. Data and materials availability: All data are available in the main text or the supplementary materials. Clinical patient data is available from F.K. ([email protected]) upon request. scRNA-seq data are available in the Gene Expression Omnibus under accession number GSE254821 (99), and metabolomics data are available in the Metabolomics Workbench data repository (100). License information: Copyright © 2025 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.science.org/about/science-licenses-journal-article-reuse We thank all members of the Inflammation Laboratory at GIMM for insightful technical and intellectual contributions, GIMM flow cytometry, and use of the animal facility. We thank D. R. de Waart (University of Amsterdam) for quantification of unconjugated bilirubin by high-performance liquid chromatography (not shown); A. Vaidya (Drexel University) for kindly providing the PfD10 and PfD10TgDHODH strains and for insightful advice; the Centre de Recherches Médicales de Lambaréné for support of the DEMIT study; L. Bardtke, P. Kroneberg, A. K. Kneller, N. Schirra, J. L. Schöllgen, and C. Conrad for sample and data processing at Charité – Universitätsmedizin Berlin; O. Chertkov (Católica Biomedical Research Centre, Portugal); the Protein Purification Research Facility and the Bacterial Imaging Cluster at ITQB NOVA for support for protein purification and quantification; and A. Malheiro (Advanced Electron Microscopy, Imaging and Spectroscopy – AEMIS) for use of the INL User Facilities. This work was supported by Fundação para a Ciência e Tecnologia (2020.04797.BD and COVID/BD/153665/2024 to A.F.; GHTMUID/04413/2020, LA-REAL-LA/P/0117/2020, and 2022.02426.PTDC to F.N.; FEDER/29411/2017 to S.R.; 2020.04797.BD to D.D.; UIDB/04565/2020, LA/P/0140/2020, and 2022.03627.PTDC to S.P.; 2022.08590.PTDC_ EXPL (DOI 10.54499/2022.08590.PTDC) to J.K.; 2021.03494.CEECIND (DOI10.54499/2021. 03494.CEECIND/CP1674/CT0004) to R.M.; 2023.09168.CEECID to E.J.; and FEDER/29411/ 2017, PTDC/MED-FSL/4681/2020 (DOI 10.54499/PTDC/MED-FSL/4681/2020), 2022.02426.PTDC (DOI 10.54499/2022.02426.PTDC), and Congento LISBOA-01-0145-FEDER-022170 to M.P.S. This work was also supported by European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie (955321 to A.G.G.S., 753236 to R.M.); DFG Cluster of Excellence “Balance of the Microverse” EXC 2051; 390713860 (E.J., M.P.S. as associated member); DFG IRTG 2290 “Molecular interactions in malaria” (P.T.-L., F.K., and the DEMIT study); Gulbenkian Foundation (S.R., M.P.S., and I.B.B. 2021-51/ BI-D/2021 to S.T.); la Caixa Foundation HR18-00502 (E.J., J.K., M.P.S.); Human Frontier Science Program (LT0043/2022-L to J.K.); Lise Meitner Excellence Programme of the Max Planck Society (S.P.); European Molecular Biology Organization (EMBO Long-term Fellowship ALTF290-2017 to R.M.); European Union’s Horizon 2020 research and innovation programme (grant 955321); Academy of Finland (grant 329278 to L.L.E.); Sigrid Juselius Foundation (L.L.E.); Biocenter Finland (L.L.E.); ELIXIR Finland (L.L.E.); American Heart Association/Paul Allen Frontiers Group (project 19PABH134580006 to B.D.P.); NIH/NIA (B.D.P. by 1R21AG073684-01 and R01AG071512); The Johns Hopkins Catalyst Award (B.D.P.); Solve ME/ CFS Initiative (grant 90089823 to B.D.P.); US Public Health Service (grant DA044123 to B.D.P.); European Research Council (grant 101001521 to M.J.A.); Oeiras-ERC Frontier Research Incentive Awards (M.P.S.); and H2020-WIDESPREAD-2020-5-952537 SymbNET Research Grants (M.P.S.).
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