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

Autor(en): Wiese, Melanie
Gerlach, Roman G.
Popp, Isabel
Matuszak, Jasmin
Mahapatro, Mousumi
Castiglione, Kirstin
Chakravortty, Dipshikha
Willam, Carsten
Hensel, Michael 
Bogdan, Christian
Jantsch, Jonathan
Stichwörter: ACTIVATION; GAS TENSIONS; HIF-1-ALPHA; Immunology; Infectious Diseases; METABOLISM; MICROBICIDAL ACTIVITY; NADPH OXIDASE; NITRIC-OXIDE SYNTHASE; PERITONEAL-MACROPHAGES; REACTIVE OXYGEN; STAPHYLOCOCCUS-AUREUS INFECTION
Erscheinungsdatum: 2012
Herausgeber: AMER SOC MICROBIOLOGY
Journal: INFECTION AND IMMUNITY
Volumen: 80
Ausgabe: 4
Startseite: 1455
Seitenende: 1466
Zusammenfassung: 
In infected tissues oxygen tensions are low. As innate immune cells have to operate under these conditions, we analyzed the ability of macrophages (M phi) 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 M phi 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 M phi. 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 M phi, respectively. Accordingly, inhibition of the respiratory chain of S. aureus-infected, normoxic PHOX-/- NOS2(-/-) M phi further raised the bacterial burden of the cells, which reached the level measured in hypoxic PHOX-/- NOS2(-/-) M phi 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.
ISSN: 00199567
DOI: 10.1128/IAI.05972-11

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