A metabolite-based resistance mechanism against malaria

• 成果类型: Article
• 署名作者: Figueiredo, Ana; Rastogi, Sonia Trikha; Ramos, Susana; Nogueira, Fatima; De Villiers, Katherine; de Sousa, Antonio G. Goncalves; Votborg-Novel, Lasse; von Wedel, Cacilie; Tober-Lau, Pinkus; Jentho, Elisa; Pagnotta, Sara; Mesquita, Miguel; Cardoso, Silvia; Bortolussi, Giulia; Muro, Andres F.; Tranfield, Erin M.; Thibaud, Jessica; Duarte, Denise; Sousa, Ana Laura; Pinto, Sandra N.; Kitoko, Jamil; Mombo-Ngoma, Ghyslain; Mischlinger, Johannes; Junttila, Sini; Alenquer, Marta; Amorim, Maria Joao; Vasavda, Chirag; Bosma, Piter J.; Violante, Sara; Drotleff, Bernhard; Paixao, Tiago; Portugal, Silvia; Kurth, Florian; Elo, Laura L.; Paul, Bindu D.; Martins, Rui; Soares, Miguel P.
• 署名单位: Instituto Superior de Ciencias da Saude Egas Moniz; Universidade Nova de Lisboa; Institute of Hygiene & Tropical Medicine - UNL; Stellenbosch University; University of Turku; Abo Akademi University; Max Planck Society; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Friedrich Schiller University of Jena; International Center for Genetic Engineering & Biotechnology (ICGEB); Universidade de Lisboa; Universidade de Lisboa; Leibniz Association; Bernhard Nocht Institut fur Tropenmedizin; University of Hamburg; University Medical Center Hamburg-Eppendorf; University of Hamburg; University Medical Center Hamburg-Eppendorf; Universidade Catolica Portuguesa; Johns Hopkins University; University of Amsterdam; European Molecular Biology Laboratory (EMBL); University of Turku; Johns Hopkins University; Johns Hopkins University; Flanders Institute for Biotechnology (VIB); Ghent University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11941
• DOI: 10.1126/science.adq6741
• 发表日期: 2025-06-12
• 关键词: rna-seq data; plasmodium-falciparum; bilirubin udp-glucuronosyltransferase-1; biliverdin reductase; heme oxygenase-1; labile heme; genome-wide; pathogenesis; association; inhibition

摘要

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.