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Cell Rep. 2014 Jul 10;8(1):126-36. doi: 10.1016/j.celrep.2014.05.054. Epub 2014 Jun 26.

Control of disease tolerance to malaria by nitric oxide and carbon monoxide.

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Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
Faculty of Medicine, Institute of Anatomy, 04103 Leipzig, Germany.
Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. Electronic address:


Nitric oxide (NO) and carbon monoxide (CO) are gasotransmitters that suppress the development of severe forms of malaria associated with Plasmodium infection. Here, we addressed the mechanism underlying their protective effect against experimental cerebral malaria (ECM), a severe form of malaria that develops in Plasmodium-infected mice, which resembles, in many aspects, human cerebral malaria (CM). NO suppresses the pathogenesis of ECM via a mechanism involving (1) the transcription factor nuclear factor erythroid 2-related factor 2 (NRF-2), (2) induction of heme oxygenase-1 (HO-1), and (3) CO production via heme catabolism by HO-1. The protection afforded by NO is associated with inhibition of CD4(+) T helper (TH) and CD8(+) cytotoxic (TC) T cell activation in response to Plasmodium infection via a mechanism involving HO-1 and CO. The protective effect of NO and CO is not associated with modulation of host pathogen load, suggesting that these gasotransmitters establish a crosstalk-conferring disease tolerance to Plasmodium infection.

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