A central role for free heme in the pathogenesis of severe malaria: the missing link?
Malaria, the disease caused by Plasmodium infection, is endemic to poverty in so-called underdeveloped countries. Plasmodium falciparum, the main infectious Plasmodium species in sub-Saharan countries, can trigger the development of severe malaria, including cerebral malaria, a neurological syndrome that claims the lives of more than one million children (<5 years old) per year. Attempts to eradicate Plasmodium infection, and in particular its lethal outcomes, have so far been unsuccessful. Using well-established rodent models of malaria infection, we found that survival of a Plasmodium-infected host is strictly dependent on the host's ability to up-regulate the expression of heme oxygenase-1 (HO-1 encoded by the gene Hmox1). HO-1 is a stress-responsive enzyme that catabolizes free heme into biliverdin, via a reaction that releases Fe and generates the gas carbon monoxide (CO). Generation of CO through heme catabolism by HO-1 prevents the onset of cerebral malaria. The protective effect of CO is mediated via its binding to cell-free hemoglobin (Hb) released from infected red blood cells during the blood stage of Plasmodium infection. Binding of CO to cell-free Hb prevents heme release and thus generation of free heme, which we found to play a central role in the pathogenesis of cerebral malaria. We will address hereby how defense mechanisms that prevent the deleterious effects of free heme, including the expression of HO-1, impact on the pathologic outcome of Plasmodium infection and how these may be used therapeutically to suppress its lethal outcomes.
Ferreira
Ana
A
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Balla
József
J
Jeney
Viktória
V
Balla
György
G
Soares
Miguel P
MP
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism; D004195:Disease Models, Animal; D006418:Heme / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D016779:Malaria, Cerebral / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D008954:Models, Biological
D006454:Hemoglobins; D006418:Heme; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1