title: 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.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreira
authors.forename: Ivo
authors.initials: I
authors.lastname: Marguti
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.forename: Viktória
authors.initials: V
authors.lastname: Jeney
authors.forename: Angelo
authors.initials: A
authors.lastname: Chora
authors.forename: Nuno R
authors.initials: NR
authors.lastname: Palha
authors.forename: Sofia
authors.initials: S
authors.lastname: Rebelo
authors.forename: Annie
authors.initials: A
authors.lastname: Henri
authors.forename: Yves
authors.initials: Y
authors.lastname: Beuzard
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002248:Carbon Monoxide / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006451:Hemoglobin, Sickle / Q000276:immunology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008288:Malaria / Q000276:immunology* / Q000503:physiopathology; D016779:Malaria, Cerebral / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010962:Plasmodium berghei
chemical_list: D018925:Chemokines; D006451:Hemoglobin, Sickle; D051267:NF-E2-Related Factor 2; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1