A metabolite-based resistance mechanism against malaria.
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| Title: | A metabolite-based resistance mechanism against malaria. |
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| Authors: | Figueiredo, Ana, Rastogi, Sonia Trikha, Ramos, Susana, Nogueira, Fátima, De Villiers, Katherine, de Sousa, António G. Gonçalves, Votborg-Novél, Lasse, von Wedel, Cäcilie, Tober-Lau, Pinkus, Jentho, Elisa, Pagnotta, Sara, Mesquita, Miguel, Cardoso, Silvia, Bortolussi, Giulia, Muro, Andrés F., Tranfield, Erin M., Thibaud, Jessica, Duarte, Denise, Sousa, Ana Laura, Pinto, Sandra N. |
| Source: | Science. 6/12/2025, Vol. 388 Issue 6752, p1-17. 17p. |
| Subjects: | Jaundice, Plasmodium falciparum, Malaria, Suppressor mutation, Bilirubin |
| Abstract: | Jaundice is a common presentation of Plasmodiumfalciparum 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. Editor's summary: Plasmodium parasites that cause malaria invade and replicate in red blood cells, causing hemolysis. Parasites detoxify the iron-rich, redox conditions by converting heme into inert hemozoin crystals. However, some people infected with malaria develop jaundice, which indicates that they are detoxifying heme by an alternative route that results in bilirubin production. Figueiredo et al. found that people with malaria inhibit bilirubin conjugation, which indicates that jaundice in malaria might be advantageous (see the Perspective by Kloehn and Soldati-Favre). Experiments in mice showed that unconjugated bilirubin enters the parasite's cells to disrupt its food vacuole and mitochondria, inhibit pyrimidine synthesis and hemozoin crystallization, and suppress replication. Therefore, it appears that jaundice has an evolutionary advantage for humans living in regions with malaria. —Caroline Ash INTRODUCTION: Jaundice arises when bilirubin, a yellow pigment, accumulates in plasma and gives a yellowish color to the skin and the sclera (the white portion of the eyeball). Bilirubin has long been considered as a "waste product" of heme catabolism. Because of its lipophilic nature, bilirubin excretion requires conjugation to glucuronic acid through a reaction catalyzed in hepatocytes by UDP glucuronosyltransferase family 1 member A1 (UGT1A1). The less toxic water-soluble conjugated bilirubin is then excreted via the bile into the intestinal lumen. Because bilirubin conjugation occurs in the liver, its accumulation in plasma is a reliable biomarker of liver dysfunction. Although accurate, this has led to the widespread perception of jaundice being a maladaptive and eventually pathogenic response. However, several investigators have shown that bilirubin participates in various activities, acting as a lipophilic antioxidant and presumably as a ligand of receptors involved in different metabolic functions. RATIONALE: Jaundice is a common presentation of malaria, the ancestral infectious disease caused by parasites from the Plasmodium genus. These parasites evolved to invade and proliferate inside the red blood cells of their hosts, causing hemolysis and the accumulation of extracellular hemoglobin in plasma. When the prosthetic heme groups of hemoglobin are detached from the globin chains of hemoglobin, there is an accumulation of labile heme in plasma, an independent risk factor for Plasmodium falciparum malaria severity. Survival from experimental malaria is contingent on the capacity of the infected host to catabolize heme into biliverdin, the substrate used by biliverdin reductase to produce bilirubin. This raised the hypothesis that bilirubin production by biliverdin reductase participates in a metabolism-based defense strategy against malaria. RESULTS: Using a highly specific approach to measure bilirubin in plasma, we found a correlation between the levels of circulating unconjugated bilirubin and the onset of symptomatic P. falciparum malaria in humans. We established that bilirubin is protective against malaria in an experimental model of malaria in mice, where repressing bilirubin production through genetic loss of function of biliverdin reductase precipitated malaria mortality. This lethal phenotype could be reversed by the administration of bilirubin, verifying that unconjugated bilirubin can be protective against experimental malaria. Repression of bilirubin conjugation by hepatic UGT1A1 was also protective against experimental malaria in mice, further supporting the protective effect of unconjugated bilirubin against malaria. Using several orthogonal approaches in vivo and in vitro, we found that unconjugated bilirubin targets Plasmodium inside the red blood cell to repress its proliferation and virulence. Bilirubin targets the parasite's mitochondrion and simultaneously interferes with heme detoxification, disrupting the parasite food vacuole and therefore inhibiting the acquisition of essential amino acids from hemoglobin. CONCLUSION: The induction of bilirubin production and inhibition of its conjugation in response to Plasmodium spp. infection is an evolutionarily conserved resistance mechanism against malaria. Presumably, this metabolism-based defense strategy has a major evolutionary trade-off, namely, the insidious incidence of neonatal jaundice, which can potentially damage neurons in the brain. To what extent this defense strategy can be targeted therapeutically to overcome the enormous burden imposed by malaria on human populations remains to be established. Antimalarial effect of bilirubin.: Malaria is associated with hemolysis and labile heme accumulation, which is catabolized into biliverdin by heme oxygenase-1 (HO-1) and converted into bilirubin by biliverdin reductase A (BVRA). Repression of bilirubin conjugation by UGT1A1 increases unconjugated bilirubin to target the Plasmodium mitochondrion and inhibit hemozoin crystallization, compromising the parasite's food vacuole and amino acid (AA) acquisition. Δψ, mitochondrial membrane potential. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Jaundice is a common presentation of Plasmodiumfalciparum 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. Editor's summary: Plasmodium parasites that cause malaria invade and replicate in red blood cells, causing hemolysis. Parasites detoxify the iron-rich, redox conditions by converting heme into inert hemozoin crystals. However, some people infected with malaria develop jaundice, which indicates that they are detoxifying heme by an alternative route that results in bilirubin production. Figueiredo et al. found that people with malaria inhibit bilirubin conjugation, which indicates that jaundice in malaria might be advantageous (see the Perspective by Kloehn and Soldati-Favre). Experiments in mice showed that unconjugated bilirubin enters the parasite's cells to disrupt its food vacuole and mitochondria, inhibit pyrimidine synthesis and hemozoin crystallization, and suppress replication. Therefore, it appears that jaundice has an evolutionary advantage for humans living in regions with malaria. —Caroline Ash INTRODUCTION: Jaundice arises when bilirubin, a yellow pigment, accumulates in plasma and gives a yellowish color to the skin and the sclera (the white portion of the eyeball). Bilirubin has long been considered as a "waste product" of heme catabolism. Because of its lipophilic nature, bilirubin excretion requires conjugation to glucuronic acid through a reaction catalyzed in hepatocytes by UDP glucuronosyltransferase family 1 member A1 (UGT1A1). The less toxic water-soluble conjugated bilirubin is then excreted via the bile into the intestinal lumen. Because bilirubin conjugation occurs in the liver, its accumulation in plasma is a reliable biomarker of liver dysfunction. Although accurate, this has led to the widespread perception of jaundice being a maladaptive and eventually pathogenic response. However, several investigators have shown that bilirubin participates in various activities, acting as a lipophilic antioxidant and presumably as a ligand of receptors involved in different metabolic functions. RATIONALE: Jaundice is a common presentation of malaria, the ancestral infectious disease caused by parasites from the Plasmodium genus. These parasites evolved to invade and proliferate inside the red blood cells of their hosts, causing hemolysis and the accumulation of extracellular hemoglobin in plasma. When the prosthetic heme groups of hemoglobin are detached from the globin chains of hemoglobin, there is an accumulation of labile heme in plasma, an independent risk factor for Plasmodium falciparum malaria severity. Survival from experimental malaria is contingent on the capacity of the infected host to catabolize heme into biliverdin, the substrate used by biliverdin reductase to produce bilirubin. This raised the hypothesis that bilirubin production by biliverdin reductase participates in a metabolism-based defense strategy against malaria. RESULTS: Using a highly specific approach to measure bilirubin in plasma, we found a correlation between the levels of circulating unconjugated bilirubin and the onset of symptomatic P. falciparum malaria in humans. We established that bilirubin is protective against malaria in an experimental model of malaria in mice, where repressing bilirubin production through genetic loss of function of biliverdin reductase precipitated malaria mortality. This lethal phenotype could be reversed by the administration of bilirubin, verifying that unconjugated bilirubin can be protective against experimental malaria. Repression of bilirubin conjugation by hepatic UGT1A1 was also protective against experimental malaria in mice, further supporting the protective effect of unconjugated bilirubin against malaria. Using several orthogonal approaches in vivo and in vitro, we found that unconjugated bilirubin targets Plasmodium inside the red blood cell to repress its proliferation and virulence. Bilirubin targets the parasite's mitochondrion and simultaneously interferes with heme detoxification, disrupting the parasite food vacuole and therefore inhibiting the acquisition of essential amino acids from hemoglobin. CONCLUSION: The induction of bilirubin production and inhibition of its conjugation in response to Plasmodium spp. infection is an evolutionarily conserved resistance mechanism against malaria. Presumably, this metabolism-based defense strategy has a major evolutionary trade-off, namely, the insidious incidence of neonatal jaundice, which can potentially damage neurons in the brain. To what extent this defense strategy can be targeted therapeutically to overcome the enormous burden imposed by malaria on human populations remains to be established. Antimalarial effect of bilirubin.: Malaria is associated with hemolysis and labile heme accumulation, which is catabolized into biliverdin by heme oxygenase-1 (HO-1) and converted into bilirubin by biliverdin reductase A (BVRA). Repression of bilirubin conjugation by UGT1A1 increases unconjugated bilirubin to target the Plasmodium mitochondrion and inhibit hemozoin crystallization, compromising the parasite's food vacuole and amino acid (AA) acquisition. Δψ, mitochondrial membrane potential. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adq6741 |
