Hepcidin in malaria superinfection: can findings be translated to humans?

Abstract

To the Editor: With great interest we read the paper by Portugal et al.1, who reported that increased production of the iron-regulatory hormone hepcidin is responsible for inhibition of the liver-stage of malaria infection during ongoing blood-stage parasitemia. Febrile malaria in humans is indeed associated with high circulating hepcidin levels2, but, in our opinion, two aspects of this study need further consideration. First, the authors excluded a role for immune responses in preventing malaria superinfection by using mice deficient in components of various pathways of the innate and adaptive immune systems. However, the authors did not report the circulating hepcidin concentrations or hepatic hepcidin expression levels in these mice. Their model predicts that hepatic hepcidin expression would be unchanged in these mice, yet inflammatory cytokines are key inducers of hepatic hepcidin expression3,4. Moreover, confirmation of their findings in hepcidin-knockout mice would have further strengthened their conclusion5. Second, the limited data available in humans are not apparently consistent with the idea that an increase in hepcidin production inhibits liver-stage malaria infection. Chronic hepatitis C virus (HCV) infection is highly prevalent in many malaria-endemic regions, and recent evidence has shown HCV infection to be associated with reduced hepatic hepcidin expression with secondary hepatocyte iron accumulation6,7. According to the model proposed by Portugal et al.1, this would be expected to result in a favorable growth environment for liver-stage parasites. Instead, the emergence of blood-stage malaria parasites was delayed in people with HCV in Gabon8. Of course, other factors related to HCV infection, such as immunosuppression, may negate the effects of hepcidin on the liver-stage infection, and these clinical observations, therefore, do not fully refute a role for hepcidin. In conclusion, Portugal et al.1 have reported intriguing data that suggest a role for hepcidin in malaria pathogenesis beyond anemia and iron dysregulation, but additional clinical studies are needed to substantiate the claims.