Hypomorphic biliverdin reductase a mutations define bilirubin anti-malarial threshold

Area of Science:

• Biochemistry
• Immunology
• Malariology

Background:

• Jaundice, characterized by elevated bilirubin, is known to confer protection against malaria.
• Biliverdin reductase A (BVRA) is the enzyme responsible for generating bilirubin.
• BVRA possesses oxidoreductase, protein kinase, and transcriptional regulator functions.

Purpose of the Study:

• To investigate the specific role of BVRA's oxidoreductase activity in malaria protection.
• To determine the threshold of circulating bilirubin required for antimalarial effects.

Main Methods:

• Generation of mice with missense mutations (G17A and E97A) in key BVRA motifs.
• Assessment of BVRA oxidoreductase activity in mutant versus wild-type mice.
• Infection of mice with *Plasmodium chabaudi chabaudi* (Pcc) and monitoring of survival and bilirubin levels.

Main Results:

• Mutant mice with reduced BVRA oxidoreductase activity (∼80-95% reduction) experienced lethal Pcc infections.
• Wild-type mice exhibited non-lethal Pcc infections.
• Mutant mice failed to reach the protective circulating unconjugated bilirubin threshold of ~20-30 μM.

Conclusions:

• BVRA's oxidoreductase activity is crucial for its antimalarial effect.
• A specific threshold of circulating bilirubin is necessary for malaria protection.
• These findings have implications for developing new antimalarial therapies and biomarker strategies.