The interplay of nitric oxide and hemoglobin in hemolytic anemia: consequences for parasite and host during malaria

Abstract

Hemoglobin (Hb) is the protein responsible for the oxygen carrying capacity of red blood cells (RBCs). However, its iron-containing, heme prosthetic group is also capa- ble of generating radical species and reacting with nitric oxide (NO). If oxygen is present, the latter reaction results in the oxidation of the heme and the conversion of NO to nitrate. Within the RBC, Hb redox reactivity is minimized by the presence of protective enzyme systems and NO consumption by RBCs is >600 lower than that of free Hb. However, in hemolytic anemia, cell-free Hb released into the blood, which results in vasoconstric- tion and vascular dysfunction. The case of malaria is particularly interesting, because the Plasmodium parasite resides within the RBC and is surrounded by Hb, but also ruptures RBCs as part of its lifecycle, releasing cell-free Hb into the blood. In this dissertation the dual role of Hb during malaria is examined: intracellular Hb is evaluated in the context of immune-system-generated, anti-parasitic oxidative spe- xv cies (NO, superoxide, peroxynitrite), while the Hb released into the blood is considered in the context of pathogenesis. It is established that NO and reactive oxygen species (ROS) are unlikely to play an anti-parasitic role, due to the presence of large amounts of Hb within RBCs, as well as the possible existance of intrinsic protective mechanism. The cell-free Hb, on the other hand, participates in pathogenesis by scavenging NO in experi- mental severe malaria (ESM). It is determined that low NO bioavailability contributes to malaria pathogenesis and that NO restoration can protect animals from development of disease. In conclusion, the study of malaria in the context of hemolytic anemia, taking into account the toxic nature of cell-free Hb and its potency as an NO scavenger, may to lead to the development of new adjunct therapies.