FIG. 7.

Induction of heme catabolism by sickle cell trait confers disease tolerance to malaria. Sickle cell disease is a molecular disease caused by a single-point mutation in the β chain of Hb (β6Glu>Val). When present in the heterozygous form, the Hb β6Glu>Val sickle mutation is not pathogenic, conferring a survival advantage against malaria (sickle cell trait). This protective effect acts via the accumulation of low (noncytotoxic) levels of free heme in plasma that induce the expression of HO-1 via a mechanism involving the activation of the transcription factor NF-E2-related factor 2 (NRF2) (not illustrated). The CO produced via heme catabolism by HO-1 binds to cell-free Hb and prevents the accumulation of free heme following Plasmodium infection, thus suppressing the pathogenesis of severe forms of malaria. This protective effect does not interfere with parasite load revealing that sickle Hb confers disease tolerance to malaria. CO, carbon monoxide. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars