GASMALARIA · Crosstalk Between Nitric and Carbon Monoxide in Suppressing the Pathogenesis of Cerebral Malaria
FP7 — People (Marie Curie Actions)
- Duration
- 2008-07-01 → 2010-06-30
- EU contribution
- €128,191
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
Crosstalk between nitric and carbon monoxide in suppressing the pathogenesis of cerebral Malaria
The central hypothesis to be tested under this project was that the gasotransmitters nitric oxide (NO) and carbon monoxide (CO) interact functionally to modulate the pathogenesis of cerebral malaria. This hypothesis was strongly supported by the observation that NO can induce the expression of heme oxygenase-1 (HO-1), an enzyme that produces CO through heme catabolism and that suppresses the onset of cerebral malaria in mice (1, 2). Moreover, there was also evidence that CO controls the activity of NO synthases, thus modulating NO production. Dr Viktória Jeney has demonstrated unequivocally that both CO and NO can provide host tolerance against plasmodium infection, that is, these gasotransmitters provide a survival advantage against malaria without interfering with parasite burden. We also found that that the protective effect of NO depends strictly on the induction of the heme catabolysing enzyme HO 1, via activation of the transcription factor transcription factor nuclear factor erythroid 2-related factor (Nrf2). The same protective mechanism, involving Nrf2 and HO-1, explains why sickle hemoglobin confers host tolerance to plasmodium infection (2). References 1. A. Pamplona et al., Nat Med 13, 703 (Jun, 2007). 2. A. Ferreira et al., Cell In Press, (2011).
Data: CORDIS, © European Union
Project objective
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)
Original text from CORDIS.
Participants
- FUNDACAO CALOUSTE GULBENKIAN · LisboaCoordinatorPortugal
Links
Data: CORDIS, © European Union