Document Detail


Hypoxia-mediated impairment of the mitochondrial respiratory chain inhibits the bactericidal activity of macrophages.
MedLine Citation:
PMID:  22252868     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-17
Journal Detail:
Title:  Infection and immunity     Volume:  80     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-19     Completed Date:  2012-05-10     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1455-66     Citation Subset:  IM    
Affiliation:
Microbiology Institute–Clinical Microbiology, Immunology, and Hygiene, University Hospital of Erlangen and Friedrich-Alexander University, Erlangen-Nuremberg, Germany.
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MeSH Terms
Descriptor/Qualifier:
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:
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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