title: Heme oxygenase-1 affords protection against noncerebral forms of severe malaria.
abstract: Infection by Plasmodium, the causative agent of malaria, is associated with hemolysis and therefore with release of hemoglobin from RBC. Under inflammatory conditions, cell-free hemoglobin can be oxidized, releasing its heme prosthetic groups and producing deleterious free heme. Here we demonstrate that survival of a Plasmodium-infected host relies strictly on its ability to prevent the cytotoxic effects of free heme via the expression of the heme-catabolyzing enzyme heme oxygenase-1 (HO-1; encoded by the Hmox1 gene). When infected with Plasmodium chabaudi chabaudi (Pcc), wild-type (Hmox1(+/+)) BALB/c mice resolved infection and restored homeostasis thereafter (0% lethality). In contrast, HO-1 deficient (Hmox1(-/-)) BALB/c mice developed a lethal form of hepatic failure (100% lethality), similar to the one occurring in Pcc-infected DBA/2 mice (75% lethality). Expression of HO-1 suppresses the pro-oxidant effects of free heme, preventing it from sensitizing hepatocytes to undergo TNF-mediated programmed cell death by apoptosis. This cytoprotective effect, which inhibits the development of hepatic failure in Pcc-infected mice without interfering with pathogen burden, is mimicked by pharmacological antioxidants such as N-acetylcysteine (NAC). When administered therapeutically, i.e., after Pcc infection, NAC suppressed the development of hepatic failure in Pcc-infected DBA/2 mice (0% lethality), without interfering with pathogen burden. In conclusion, we describe a mechanism of host defense against Plasmodium infection, based on tissue cytoprotection against free heme and limiting disease severity irrespectively of parasite burden.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Elsa
authors.initials: E
authors.lastname: Seixas
authors.forename: Raffaella
authors.initials: R
authors.lastname: Gozzelino
authors.forename: Angelo
authors.initials: A
authors.lastname: Chora
authors.forename: Ana
authors.initials: A
authors.lastname: Ferreira
authors.forename: Gabriela
authors.initials: G
authors.lastname: Silva
authors.forename: Rasmus
authors.initials: R
authors.lastname: Larsen
authors.forename: Sofia
authors.initials: S
authors.lastname: Rebelo
authors.forename: Carmen
authors.initials: C
authors.lastname: Penido
authors.forename: Neal R
authors.initials: NR
authors.lastname: Smith
authors.forename: Antonio
authors.initials: A
authors.lastname: Coutinho
authors.forename: Miguel P
authors.initials: MP
authors.lastname: Soares
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression; D006418:Heme / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000473:pathology / Q000517:prevention & control; D008288:Malaria / Q000201:enzymology* / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016513:Mice, SCID; D018384:Oxidative Stress; D016788:Plasmodium chabaudi / Q000472:pathogenicity* / Q000502:physiology; D018183:Transplantation Chimera; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D014409:Tumor Necrosis Factor-alpha; D006418:Heme; D051547:Heme Oxygenase-1; D000111:Acetylcysteine
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