NDLI: Hypoxia-Mediated Impairment of the Mitochondrial Respiratory Chain Inhibits the Bactericidal Activity of Macrophages

Content Provider	PubMed Central
Author	Wiese, Melanie Gerlach, Roman G. Popp, Isabel Matuszak, Jasmin Mousumi, Mahapatro Castiglione, Kirstin Chakravortty, Dipshikha Willam, Carsten Hensel, Michael Bogdan, Christian Jantsch, Jonathan
Editor	Mccormick, B. A.
Copyright Year	2012
Abstract	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.
Related Links	http://dx.doi.org/10.1128/IAI.05972-11
Starting Page	1455
File Format	PDF
ISSN	10985522
e-ISSN	10985522
Journal	Infection and Immunity
Issue Number	4
Volume Number	80
Language	English
Publisher	American Society for Microbiology
Publisher Date	2012-04-01
Access Restriction	Open
Rights Holder	American Society for Microbiology
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases Parasitology Immunology Microbiology

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