Sickle hemoglobin confers tolerance to Plasmodium infection.

Abstract

Sickle human hemoglobin (Hb) confers a survival advantage to individuals living in endemic areas of malaria, the disease caused by Plasmodium infection. As demonstrated hereby, mice expressing sickle Hb do not succumb to experimental cerebral malaria (ECM). This protective effect is exerted irrespectively of parasite load, revealing that sickle Hb confers host tolerance to Plasmodium infection. Sickle Hb induces the expression of heme oxygenase-1 (HO-1) in hematopoietic cells, via a mechanism involving the transcription factor NF-E2-related factor 2 (Nrf2). Carbon monoxide (CO), a byproduct of heme catabolism by HO-1, prevents further accumulation of circulating free heme after Plasmodium infection, suppressing the pathogenesis of ECM. Moreover, sickle Hb inhibits activation and/or expansion of pathogenic CD8(+) T cells recognizing antigens expressed by Plasmodium, an immunoregulatory effect that does not involve Nrf2 and/or HO-1. Our findings provide insight into molecular mechanisms via which sickle Hb confers host tolerance to severe forms of malaria.

• Authors: Ana Ferreira, Ivo Marguti, Ingo Bechmann, Viktória Jeney, Angelo Chora, Nuno R Palha, Sofia Rebelo, Annie Henri, Yves Beuzard, Miguel P Soares
• Journal: Cell (Cell) Vol. 145 Issue 3 Pg. 398-409 (Apr 29 2011) ISSN: 1097-4172 [Electronic] United States
• PMID: 21529713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Chemokines
• Hemoglobin, Sickle
• NF-E2-Related Factor 2
• Carbon Monoxide
• Heme Oxygenase-1

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Carbon Monoxide (metabolism)
• Chemokines (metabolism)
• Crosses, Genetic
• Disease Models, Animal
• Heme Oxygenase-1 (metabolism)
• Hemoglobin, Sickle (immunology)
• Host-Pathogen Interactions
• Humans
• Malaria (immunology, physiopathology)
• Malaria, Cerebral (immunology, physiopathology)
• Mice
• Mice, Inbred C57BL
• NF-E2-Related Factor 2 (metabolism)
• Plasmodium berghei