Control of Disease Tolerance to Malaria by Nitric Oxide and Carbon Monoxide

• Published in: Cell reports (Cambridge) Vol. 8; no. 1; pp. 126 - 136
• Main Authors: Jeney, Viktória, Ramos, Susana, Bergman, Marie-Louise, Bechmann, Ingo, Tischer, Jasmin, Ferreira, Ana, Oliveira-Marques, Virginia, Janse, Chris J., Rebelo, Sofia, Cardoso, Silvia, Soares, Miguel P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-07-2014; Elsevier
• Subjects: Animals; Carbon Monoxide - metabolism; Carbon Monoxide - pharmacology; Carbon Monoxide - therapeutic use; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Immune Tolerance; Lymphocyte Activation; Malaria, Cerebral - drug therapy; Malaria, Cerebral - immunology; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nitric Oxide - pharmacology; Nitric Oxide - therapeutic use; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.05.054

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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•Nitric oxide confers disease tolerance to malaria•The protective effect of nitric oxide acts via induction of HO-1 by NRF2•Carbon monoxide generated by HO-1 mediates the protective effect of nitric oxide•The immunoregulatory effect of nitric oxide acts via HO-1 and carbon monoxide
The gaseous molecules nitric oxide (NO) and carbon monoxide (CO) are both protective against severe forms of malaria. In this study, Jeney et al. unravel functional crosstalk between these gaseous molecules in which NO induces the expression of heme oxygenase-1, which in turn produces CO and protects mice from a severe form of malaria known as cerebral malaria. These gaseous molecules do not interfere with host pathogen load but, instead, confer disease tolerance to malaria.