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Crosstalk Between Nitric and Carbon Monoxide in Suppressing the Pathogenesis of Cerebral Malaria

Final Report Summary - GASMALARIA (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).

1. A. Pamplona et al., Nat Med 13, 703 (Jun, 2007).
2. A. Ferreira et al., Cell In Press, (2011).