A metabolite-based resistance mechanism against malaria.

Abstract

Jaundice is a common presentation of <i>Plasmodium</i> <i>falciparum</i> malaria, which arises from the accumulation of circulating bilirubin. It is not understood whether it represents an adaptive or maladaptive response to <i>Plasmodium</i> spp. infection. We found that asymptomatic <i>P. falciparum</i> 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 <i>P. falciparum</i> 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 <i>Plasmodium</i> spp. infection that limits malaria severity.