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 BlvraG17A and BlvraE97A mice harboring G17A and E97A missense mutations in the BVRA NAD(P)H-binding domain and reductase motif, respectively. Both BlvraG17A and BlvraE97Amice presented a reduction in enzymatic activity and succumbed to malaria, otherwise non-lethal to wild-type (BlvraWT) 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. Highlights- 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;