Fig 5.

Heme metabolism and malaria outcomes. The diagram illustrates a summary of the major mechanisms that are triggered by hemolysis during malaria. (A) Under homeostatic conditions, the free Hb that is released by dead red blood cells is rapidly scavenged by haptoglobin, and this molecular complex is removed from the circulation by the haptoglobin-Hb receptor CD163 on the surface of monocytes and macrophages. The Hb is processed inside these cells in an event that releases heme, which is further metabolized by the antioxidant enzyme HO-1. During an acute malarial attack, there is an accumulation of circulating free hemoglobin that is not compensated for by the amount of Hp available in the blood. The excess of free Hb is then oxidized by free radicals, releasing free heme. Free heme is very toxic to the cells and induces inflammation, macrophage activation, and oxidative stress. The host homeostatic responses triggered by heme include the induction of Hp, CD163, and HO-1. (B) We found that the intensity of the malaria-related symptoms is associated with the levels of circulating free heme. The individuals who developed symptoms after Plasmodium infection exhibited higher levels of Hp, soluble CD163, and HO-1. Nevertheless, this counterregulatory response is not sufficient to reduce the amount of free heme in the plasma, which also might explain the higher inflammatory scores estimated in symptomatic patients. These susceptible individuals carried the Hp2 allele or the Hp2.2 genotype more frequently than did other individuals. In addition, they more frequently carried long GT repeats in the HMOX1 polymorphism, which are paradoxically associated with a relatively lower plasma HO-1 concentration. The individuals with clinical immunity against malaria who remained asymptomatic upon Plasmodium infection tended to carry the Hp1S allele and have short GT repeats in the HMOX1 polymorphism more frequently than the symptomatic individuals. These protected individuals still had modest elevations in the levels of free heme and haptoglobin, with no differences in the concentrations of sCD163 and HO-1 compared with noninfected individuals.