{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T18:46:38Z","timestamp":1775933198820,"version":"3.50.1"},"posted":{"date-parts":[[2025,2,26]]},"group-title":"Immunology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Whether jaundice, a common presentation of\n                  <jats:italic>Plasmodium<\/jats:italic>\n                  (\n                  <jats:italic>P<\/jats:italic>\n                  .)\n                  <jats:italic>falciparum<\/jats:italic>\n                  malaria (1-3) arising from the accumulation of circulating bilirubin, represents an adaptive or maladaptive response to\n                  <jats:italic>Plasmodium<\/jats:italic>\n                  spp. infection is not understood (1-3). We found that asymptomatic\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  infection was associated with a &gt;10-fold higher ratio of unconjugated bilirubin over parasite burden, compared to symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) (4) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, via genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1) (\n                  <jats:italic>5<\/jats:italic>\n                  ), was protective against malaria in mice. Unconjugated bilirubin inhibited\n                  <jats:italic>P. falciparum<\/jats:italic>\n                  proliferation in red blood cells (RBC) via a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin (Hz) crystallization and compromised the parasite\u2019s food vacuole. In conclusion, jaundice represents a metabolic response to\n                  <jats:italic>Plasmodium spp<\/jats:italic>\n                  . infection that limits malaria severity.\n                <\/jats:p>","DOI":"10.1101\/2025.02.20.639306","type":"posted-content","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T14:10:29Z","timestamp":1740579029000},"source":"Crossref","is-referenced-by-count":0,"title":["A Metabolite-Based Resistance Mechanism Against Malaria"],"prefix":"10.64898","author":[{"given":"Ana","family":"Figueiredo","sequence":"first","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz 1649-035 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia Trikha","family":"Rastogi","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz 1649-035 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Ramos","sequence":"additional","affiliation":[{"name":"Gulbenkian Institute for Molecular Medicine (GIMM), Avenida Professor Egas Moniz 1649-035 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F\u00e1tima","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, Rua da Junqueira 100, 1349-008 Lisboa, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"De Villiers","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Polymer Science, Stellenbosch University, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ant\u00f3nio G. 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