"Malaria, can lead to the development of cerebral malaria (CM), a lethal syndrome that claims more then one million deaths per year. There is currently no effective treatment against CM. We have shown that the gas carbon monoxide (CO), generated via heme catabolism by heme oxygenase-1, inhibits the onset of CM in mice (1). While not affecting parasitemia per se, CO inhibits all the major pathologic hallmarks of CM, including blood brain barrier disruption, brain micro-vascular congestion and neuroinflammation. The mechanism underlying this protective effect relies on the ability of CO to bind the heme groups of cell free hemoglobin, released from infected red blood cells. Once bound to these heme groups CO suppresses their release, thus devoiding them from triggering CM (1). The same heme groups contained within cell free hemoglobin have been shown to scavenge endogenous nitric oxide (NO) and decrease its bioavailability, an effect shown to precipitate the onset of CM in mice (2). This suggests that as for CO, NO can also contribute to suppresses the development of CM. The central hypothesis to be tested under this proposal is that the protective effect of NO might rely on its well-established ability to induce the expression of heme oxygenase-1 and in this manner sustain the generation of CO. Once bound to the heme groups of cell-free hemoglobin, CO would inhibit heme release and in addition would increase NO bioavailability, thus generating a protective positive feed back loop in which NO would sustain the expression of heme oxygenase-1 and the generation of CO. Unveiling this functional interaction between NO and CO during Malaria infection might be useful not only to our understanding of the basic mechanisms underlying the pathogenesis of CM but also in developing new therapeutic strategies aimed at overcoming the devastating effects of this disease. 1. A. Pamplona et al., Nat Med 13, 703 (Jun, 2007). 2. I. Gramaglia et al., Nat Med 12, 1417 (Dec, 2006)"