Heme oxygenase-1, carbon monoxide, and malaria – The interplay of chemistry and biology

Transition metals, including iron, are central to the chemistry of life, bridging inorganic chemistry and biology and playing various biochemical roles. Endogenous and biologically active ‘gases’ including NO and CO, have the remarkable ability to bind metal centers making metalloproteins and, in particular, hemoproteins one of its most common targets. Heme, an iron-centered porphyrin, is a metal prosthetic group present in various metalloproteins, including hemoglobin. Heme oxygenases are the enzymes responsible for the catabolism of heme through a unique mechanism where heme is utilized both as substrate and cofactor. Heme oxygenases play critical roles in heme homeostasis, iron recycling, and response to stress and inflammation, particularly HO-1, its inducible form. HO-1 and its by-products — biliverdin, CO, and iron — have documented antioxidant, anti-inflammatory, and immunoregulatory roles. However, during infection, HO-1 may contribute to limiting pathogen burden and prevent host damage or promote pathogen growth and infection. Malaria was one of the first infectious diseases where these two facets of HO-1 were uncovered. In models of severe malaria, HO-1 was shown to play essential roles in controlling resistance and susceptibility to experimental cerebral malaria and malaria-associated acute lung injury via the production of CO. These and other studies have supported CO as a promising therapeutic agent for a range of inflammatory conditions. However, the use of CO gas in the clinic remains questionable due to safety concerns. The emergence of CO-releasing molecules, mostly organometallic carbonyl complexes capable of delivering CO to cells and tissues in a controlled fashion, have been considered a valid alternative to CO inhalation. This review focuses on the heme/HO-1/CO pathway and its role in infectious diseases, particularly severe malaria. We also address current knowledge on the crosstalk between NO and HO-1/CO and its impact on severe malaria susceptibility. Finally, we discuss the use of CO-releasing molecules as a feasible therapeutic strategy for severe malaria and other diseases.