title: Hypoxia modulates infection of epithelial cells by Pseudomonas aeruginosa.
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.
authors: UCD School of Medicine and Medical Science and The Conway Institute, University College Dublin, Dublin, Ireland.
authors: Bettina
authors: B
authors: Schaible
authors: Siobhán
authors: S
authors: McClean
authors: Andrew
authors: A
authors: Selfridge
authors: Alexis
authors: A
authors: Broquet
authors: Karim
authors: K
authors: Asehnoune
authors: Cormac T
authors: CT
authors: Taylor
authors: Kirsten
authors: K
authors: Schaffer
mesh_terms: D000577:Amides / Q000494:pharmacology; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D018938:Caco-2 Cells; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D056945:Hep G2 Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D011550:Pseudomonas aeruginosa / Q000276:immunology* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D016019:Survival Analysis; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000577:Amides; D000600:Amino Acids, Dicarboxylic; D051792:Basic Helix-Loop-Helix Proteins; D011725:Pyridines; D020741:rho GTP-Binding Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C108830:Y 27632; C040947:oxalylglycine