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Abstract zur Publikation: Hypoxia-mediated impairment of the mitochondrial respiratory chain inhibits the bactericidal activity of macrophages

Wiese M, Gerlach RG et al. (2012): Hypoxia-mediated impairment of the mitochondrial respiratory chain inhibits the bactericidal activity of macrophages.
Infect. Immun. 80 (4): 1455-1466. Epub Jan 17. doi:10.1128/IAI.05972-11.

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 impaired the bactericidal activity of the host cells against both pathogens. This correlated with a decreased production of reactive oxygen (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 WT 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 kill 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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