Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Stolt, C; Schmidt, IH; Sayfart, Y; Steinmetz, I; Bast, A.
Heme Oxygenase-1 and Carbon Monoxide Promote Burkholderia pseudomallei Infection.
J Immunol. 2016; 197(3):834-846
Doi: 10.4049/jimmunol.1403104
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- Steinmetz Ivo
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- Abstract:
- The environmental bacterium and potential biothreat agent Burkholderia pseudomallei causes melioidosis, an often fatal infectious disease. Increased serum bilirubin has been shown to be a negative predictive factor in melioidosis patients. We therefore investigated the role of heme oxygenase-1 (HO-1), which catalyzes the degradation of heme into the bilirubin precursor biliverdin, ferrous iron, and CO during B. pseudomallei infection. We found that infection of murine macrophages induces HO-1 expression, involving activation of several protein kinases and the transcription factor nuclear erythroid-related factor 2 (Nrf2). Deficiency of Nrf2 improved B. pseudomallei clearance by macrophages, whereas Nrf2 activation by sulforaphane and tert-butylhydroquinone with subsequent HO-1 induction enhanced intracellular bacterial growth. The HO-1 inducer cobalt protoporphyrin IX diminished proinflammatory cytokine levels, leading to an increased bacterial burden in macrophages. In contrast, HO-1 gene knockdown reduced the survival of intramacrophage B. pseudomallei Pharmacological administration of cobalt protoporphyrin IX to mice resulted in an enhanced bacterial load in various organs and was associated with higher mortality of intranasally infected mice. The unfavorable outcome of B. pseudomallei infection after HO-1 induction was associated with higher serum IL-6, TNF-α, and MCP-1 levels but decreased secretion of IFN-γ. Finally, we demonstrate that the CO-releasing molecule CORM-2 increases the B. pseudomallei load in macrophages and mice. Thus, our data suggest that the B. pseudomallei-mediated induction of HO-1 and the release of its metabolite CO impair bacterial clearance in macrophages and during murine melioidosis. Copyright © 2016 by The American Association of Immunologists, Inc.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Blotting, Western -
- Burkholderia pseudomallei -
- Carbon Monoxide - metabolism
- Cytokines - biosynthesis
- Disease Models, Animal -
- Flow Cytometry -
- Fluorescent Antibody Technique -
- Gene Knockdown Techniques -
- Heme Oxygenase-1 - biosynthesis
- Macrophages - metabolism
- Macrophages - microbiology
- Melioidosis - metabolism
- Melioidosis - pathology
- Mice -
- Mice, Inbred C57BL -
- Organometallic Compounds - metabolism
- Real-Time Polymerase Chain Reaction -