| Hypoxia-mediated impairment of the mitochondrial respiratory chain inhibits the bactericidal activity of macrophages. | |
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MedLine Citation:
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PMID: 22252868 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In infected tissues oxygen tensions are low. As innate immune cells have to operate under these conditions, we analyzed the ability of macrophages (Mφ) to kill Escherichia coli or Staphylococcus aureus in a hypoxic microenvironment. Oxygen restriction did not promote intracellular bacterial growth but did impair the bactericidal activity of the host cells against both pathogens. This correlated with a decreased production of reactive oxygen intermediates (ROI) and reactive nitrogen intermediates. Experiments with phagocyte NADPH oxidase (PHOX) and inducible NO synthase (NOS2) double-deficient Mφ revealed that in E. coli- or S. aureus-infected cells the reduced antibacterial activity during hypoxia was either entirely or partially independent of the diminished PHOX and NOS2 activity. Hypoxia impaired the mitochondrial activity of infected Mφ. Inhibition of the mitochondrial respiratory chain activity during normoxia (using rotenone or antimycin A) completely or partially mimicked the defective antibacterial activity observed in hypoxic E. coli- or S. aureus-infected wild-type Mφ, respectively. Accordingly, inhibition of the respiratory chain of S. aureus-infected, normoxic PHOX(-/-) NOS2(-/-) Mφ further raised the bacterial burden of the cells, which reached the level measured in hypoxic PHOX(-/-) NOS2(-/-) Mφ cultures. Our data demonstrate that the reduced killing of S. aureus or E. coli during hypoxia is not simply due to a lack of PHOX and NOS2 activity but partially or completely results from an impaired mitochondrial antibacterial effector function. Since pharmacological inhibition of the respiratory chain raised the generation of ROI but nevertheless phenocopied the effect of hypoxia, ROI can be excluded as the mechanism underlying the antimicrobial activity of mitochondria. |
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Authors:
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Melanie Wiese; Roman G Gerlach; Isabel Popp; Jasmin Matuszak; Mousumi Mahapatro; Kirstin Castiglione; Dipshikha Chakravortty; Carsten Willam; Michael Hensel; Christian Bogdan; Jonathan Jantsch |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2012-01-17 |
Journal Detail:
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Title: Infection and immunity Volume: 80 ISSN: 1098-5522 ISO Abbreviation: Infect. Immun. Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-03-19 Completed Date: 2012-05-10 Revised Date: 2013-02-08 |
Medline Journal Info:
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Nlm Unique ID: 0246127 Medline TA: Infect Immun Country: United States |
Other Details:
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Languages: eng Pagination: 1455-66 Citation Subset: IM |
Affiliation:
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Microbiology Institute–Clinical Microbiology, Immunology, and Hygiene, University Hospital of Erlangen and Friedrich-Alexander University, Erlangen-Nuremberg, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Hypoxia* Electron Transport Escherichia coli / growth & development, immunology* Macrophages / immunology*, metabolism*, microbiology Membrane Potential, Mitochondrial Mice Mice, Inbred C57BL Mice, Knockout Mitochondria / metabolism* NADPH Oxidase / deficiency, genetics, metabolism Nitric Oxide Synthase Type II / genetics, metabolism RNA Interference RNA, Small Interfering Reactive Nitrogen Species / biosynthesis, metabolism* Reactive Oxygen Species / metabolism* Staphylococcus aureus / growth & development, immunology* |
| Chemical | |
Reg. No./Substance:
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0/RNA, Small Interfering; 0/Reactive Nitrogen Species; 0/Reactive Oxygen Species; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.6.3.1/NADPH Oxidase |
| Comments/Corrections | |
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