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A Metabolite-Based Resistance Mechanism Against Malaria

ABSTRACT: Severe presentations of malaria, arising from Plasmodium spp. infection, are often associated with accumulation of circulating bilirubin, a condition known as hyperbilirubinemia or jaundice of malaria. Whether this represents an adaptive or maladaptive response to Plasmodium spp. infection is not understood. Departing from the textbook view of hyperbilirubinemia reflecting a failure to excrete bilirubin, we demonstrate that bilirubin production by biliverdin reductase A (BLVRA) partakes in a host adaptive response to malaria. Genetic Blvra deletion exacerbated malaria mortality in mice; This was associated with a >10-fold increase in parasite burden, compared to control mice expressing BLVRA, which cleared the parasite and survived malaria. At concentrations in the range of jaundice of malaria, unconjugated bilirubin arrested the proliferation and killed asexual blood stages of the human-infective P. falciparum in vitro. This was associated with disruption of the parasite’s mitochondrion and food vacuole as well as with the accumulation of hemozoin in the parasite’s cytoplasm. Moreover, bilirubin inhibited hemozoin (β-hematin) synthesis in vitro, a vital heme-detoxifying pathway targeted by Quinoline-based antimalarial drugs such as chloroquine. In conclusion, hyperbilirubinemia represents an evolutionary conserved metabolite-based resistance mechanism against malaria.

ORGANISM(S): Mus musculus

PROVIDER: GSE254821 | GEO | 2025/03/24

REPOSITORIES: GEO

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Project description:Neonatal hyperbilirubinemia (jaundice) is common in infants, with extremely preterm infants (EPT, <28 weeks gestational age) being at high risk for bilirubin-induced neurotoxicity, resulting in neurodevelopmental impairment. Hyperbilirubinemia is treated using phototherapy to lower unconjugated bilirubin levels. However, the benefits and risks of phototherapy in EPTs have not been well studied, and bilirubin at low levels may be protective as an antioxidant. Phototherapy is associated with markers of oxidative stress in the plasma, but the effects of phototherapy on the hippocampus (HPC) are not known. Bilirubin and insults associated with EPTs impair hippocampal development, a brain structure critical for cognitive function, but their underlying mechanisms remain unknown. The effects of hyperbilirubinemia and phototherapy on the HPC were studied using a Gunn rat model. Jaundiced (jj) and non-jaundiced (Nj) pups were subjected to phototherapy from postnatal day 4 (P4) through P6. The HPC was harvested and processed for RNA sequencing. Serum bilirubin levels were elevated in jj compared to Nj control rats. Phototherapy significantly lowered serum bilirubin levels in jj rats. Compared to Nj rats, 1294 genes were differentially expressed in the jj hippocampal transcriptome and mapped onto the nervous system development, inflammation, and ferroptosis signaling pathways. Phototherapy induces 3297 differentially-expressed genes (DEGs) in rat hippocampal transcriptome compared to untreated rats. These DEGs were annotated to pathways regulating synaptogenesis, long-term potentiation, and neurogenesis. Both hyperbilirubinemia and phototherapy altered expression of 407 genes, which mapped onto hippocampal plasticity functions, including neuritogenesis and long-term potentiation. Our study demonstrates a model for investigating molecular effects of hyperbilirubemia and phototherapy in an EPT-equivalent Gunn rat pup. Our data revealed the effects of hyperbilirubinemia and phototherapy on signaling pathways critical for hippocampal development and plasticity.

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A Metabolite-Based Resistance Mechanism Against Malaria

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