Biliverdin Reductase Catalytic Activity Is Essential for Malaria Resistance

Jaundice, a condition characterized by elevated levels of circulating bilirubin, is an adaptive response to malaria sustained through bilirubin production by biliverdin reductase A (BVRA). Beyond its enzymatic activity, BVRA acts as a protein kinase and as a transcription factor. To disentangle the contribution of BVRA catalytic activity over its non-canonical functions we generated Blvra ^G17A and Blvra ^E97A mice harboring G17A and E97A missense mutations in the BVRA NAD(P)H-binding domain and reductase motif, respectively. Both Blvra ^G17A and Blvra ^E97A mice presented a reduction in enzymatic activity and succumbed to malaria, otherwise non-lethal to wild-type ( Blvra ^WT ) mice. Quantification of circulating unconjugated bilirubin revealed a dose response effect whereby the mutant strains failed to reach a threshold of circulating bilirubin required to support its protective effect. These findings establish the antimalarial effect of the enzymatic activity of BVRA and define a concentration threshold of bilirubin required for malaria protection, informing therapeutic development and biomarker-guided malaria treatment strategies.

- Establishment of catalytic deficient BVRA mouse mutants;- Anti-malarial effect of BVRA relies on its catalytic activity;- A minimal bilirubin threshold for parasite control;- A minimal bilirubin threshold for malaria resolution.