title: Heme catabolism by heme oxygenase-1 confers host resistance to Mycobacterium infection.
abstract: Heme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1 isoform, encoded by the Hmox1 gene, is required for host protection against systemic infections. Here we report that upregulation of HO-1 expression in macrophages (M) is strictly required for protection against mycobacterial infection in mice. HO-1-deficient (Hmox1(-/-)) mice are more susceptible to intravenous Mycobacterium avium infection, failing to mount a protective granulomatous response and developing higher pathogen loads, than infected wild-type (Hmox1(+/+)) controls. Furthermore, Hmox1(-/-) mice also develop higher pathogen loads and ultimately succumb when challenged with a low-dose aerosol infection with Mycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed in M. avium-infected Hmox1(-/-) versus Hmox1(+/+) SCID mice lacking mature B and T cells. In the absence of HO-1, heme accumulation acts as a cytotoxic pro-oxidant in infected M, an effect mimicked by exogenous heme administration to M. avium-infected wild-type M in vitro or to mice in vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in M, contributing critically to host resistance to Mycobacterium infection.
authors: Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. sgomes@ibmc.up.pt
authors: Sandro
authors: S
authors: Silva-Gomes
authors: Rui
authors: R
authors: Appelberg
authors: Rasmus
authors: R
authors: Larsen
authors: Miguel Parreira
authors: MP
authors: Soares
authors: Maria Salomé
authors: MS
authors: Gomes
mesh_terms: D000818:Animals; D058491:Bacterial Load; D016923:Cell Death; D002478:Cells, Cultured; D060467:Disease Resistance / Q000276:immunology*; D006099:Granuloma / Q000201:enzymology / Q000276:immunology; D006418:Heme / Q000378:metabolism* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D050296:Microbial Viability; D009162:Mycobacterium avium / Q000276:immunology / Q000472:pathogenicity*; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity*; D018384:Oxidative Stress; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
chemical_list: D008565:Membrane Proteins; D006418:Heme; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
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