Severe Malaria Increases the List of Heme Oxygenase-1-Protected diseases

Abstract

Malaria is the most widespread and lethal parasitic disease in the world today, and claims the lives of at least 1 million people every year. The disease is caused by parasitic protozoa of the genus Plasmodium, whose life cycle involves a vertebrate host and a mosquito vector. The parasite undergoes two different stages of infection within the mammalian host. The first stage occurs inside hepatocytes and is clinically asymptomatic. The symptoms associated with the disease appear only during the subsequent stage of infection, which occurs inside erythrocytes. In humans, clinical manifestations of malaria can range from mild to severe malaria, the latter comprising a series of syndromes that include, among others, cerebral malaria (CM) and acute respiratory distress syndrome. Interestingly, although four Plasmodium species infect humans (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale), only one of these parasites, P. falciparum, causes fatal disease. The reason(s) for this difference are yet to be fully elucidated. The sequestration of infected erythrocytes in vital organs, a feature unique to P. falciparum infection, has been identifed as a major factor. However, whether this feature causes disease due to mechanical blockage of blood flow or to the release of inflammatory mediators in vulnerable regions caused by local infected-erythrocyte rupture, is still a matter of controversy [1], and increasing evidence is suggesting a role for inflammatory mediators in malaria-associated pathology [2]. Thus, it has been proposed that the pathogenesis of malaria might not differ much from other clinically overlapping systemic diseases caused by other pathogens or even nonpathogen-dependent inflammatory syndromes [3]. Recently, we have used mice infected with Plasmodium berghei ANKA, a rodent model of malaria pathology, to demonstrate that the antiinflammatory molecule heme oxygenase (HO)-1, which degrades heme to generate biliverdin, iron and carbon monoxide (CO), prevents the development of experimental CM (ECM) [4]. Moreover, we demonstrated that exposure to the endproduct of HO-1 activity, CO, also protected mice against ECM [4]. The anti-inflammatory effects of HO-1 activation were first reported in experimental sepsis [5], and later extended to inflammation in general [6]. Again, in these cases, CO was shown to be the mediator molecule between HO-1 activity and protection against inflammation [6]. More recently, it was postulated that the inhibitory effects of CO observed in systemic inflammation, and the role of TNF-induced HO-1, might also play a role in a malarial context [3]. In fact, HO-1 was detected in histological sections from human sepsis and malaria cases [7].