Hypoxia modulates infection of epithelial cells by Pseudomonas aeruginosa

PLoS One. 2013;8(2):e56491. doi: 10.1371/journal.pone.0056491. Epub 2013 Feb 13.

Abstract

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen commonly associated with lung and wound infections. Hypoxia is a frequent feature of the microenvironment of infected tissues which induces the expression of genes associated with innate immunity and inflammation in host cells primarily through the activation of the hypoxia-inducible factor (HIF) and Nuclear factor kappaB (NF-κB) pathways which are regulated by oxygen-dependent prolyl-hydroxylases. Hypoxia also affects virulence and antibiotic resistance in bacterial pathogens. However, less is known about the impact of hypoxia on host-pathogen interactions such as bacterial adhesion and infection. In the current study, we demonstrate that hypoxia decreases the internalization of P. aeruginosa into cultured epithelial cells resulting in decreased host cell death. This response can also be elicited by the hydroxylase inhibitor Dimethyloxallyl Glycine (DMOG). Reducing HIF-2α expression or Rho kinase activity diminished the effects of hypoxia on P. aeruginosa infection. Furthermore, in an in vivo pneumonia infection model, application of DMOG 48 h before infection with P. aeruginosa significantly reduced mortality. Thus, hypoxia reduces P. aeruginosa internalization into epithelial cells and pharmacologic manipulation of the host pathways involved may represent new therapeutic targets in the treatment of P. aeruginosa infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology
  • Amino Acids, Dicarboxylic / pharmacology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blotting, Western
  • Caco-2 Cells
  • Cell Hypoxia
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Endocytosis / drug effects
  • Endocytosis / immunology
  • Epithelial Cells / immunology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Hep G2 Cells
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / immunology
  • Humans
  • Lung / drug effects
  • Lung / immunology
  • Lung / metabolism
  • Mice
  • Pneumonia / immunology*
  • Pneumonia / microbiology
  • Pneumonia / prevention & control
  • Pseudomonas Infections / immunology*
  • Pseudomonas Infections / microbiology
  • Pseudomonas Infections / prevention & control
  • Pseudomonas aeruginosa / immunology*
  • Pseudomonas aeruginosa / physiology
  • Pyridines / pharmacology
  • RNA Interference
  • Survival Analysis
  • rho GTP-Binding Proteins / antagonists & inhibitors
  • rho GTP-Binding Proteins / immunology
  • rho GTP-Binding Proteins / metabolism

Substances

  • Amides
  • Amino Acids, Dicarboxylic
  • Basic Helix-Loop-Helix Transcription Factors
  • Pyridines
  • Y 27632
  • endothelial PAS domain-containing protein 1
  • rho GTP-Binding Proteins
  • oxalylglycine

Grant support

This work was supported by grants from the Irish Research Council for Science, Engineering & Technology, and Science Foundation Ireland. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.