title: Growth inhibition of multiresistant enterococci by interferon-gamma-activated human uro-epithelial cells.
abstract: Nosocomial infections with enterococci are an increasing problem in modern medical practice due to the development of resistance to a wide range of antibiotics, including the glycopeptides vancomycin and teicoplanin. An increasing number of vancomycin-resistant enterococci (VRE) have been cultured from clinical specimens -- especially from patients undergoing immunosuppressive therapy -- and bacteraemia caused by these VRE, subsequent to colonisation of epithelial surfaces, is a significant cause of mortality in such patients. Recent evidence showed that the induction of indoleamine 2,3 dioxygenase (IDO) by interferon-gamma (IFN-gamma) inhibited growth of group B streptococci by depleting the essential amino acid L-tryptophan. This study describes the IFN-gamma-induced expression of IDO -- shown at a transcriptional level by Northern blot analysis, at translational level by Western blot and also at a functional level by L-tryptophan degradation to L-kynurenine -- in the uro-epithelial cell line RT4. The depletion of L-tryptophan resulted in growth inhibition of enterococci, and this was confirmed by abrogation of the inhibitory effect by re-supplementation with excess L-tryptophan. Multiresistant enterococci, including vancomycin-resistant strains resistant to all commercially available antibiotics, were inhibited by the IFN-gamma-induced expression of IDO and subsequent L-tryptophan degradation. This may be an important mechanism in the local restriction of colonisation of the urinary tract by endogenous enterococci and in inhibiting the spread of the bacteria beyond the epithelial barrier.
authors.affiliation: Institute for Medical Microbiology and Virology, Heinrich-Heine University, Universitätsstraße 1, 40225 Düsseldorf, Germany.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Mackenzie
authors.affiliation: Institute for Medical Microbiology and Virology, Heinrich-Heine University, Universitätsstraße 1, 40225 Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hucke
authors.affiliation: Institute for Medical Microbiology and Virology, Heinrich-Heine University, Universitätsstraße 1, 40225 Düsseldorf, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: MÜller
authors.affiliation: Institute for Medical Microbiology and Virology, Heinrich-Heine University, Universitätsstraße 1, 40225 Düsseldorf, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Seidel
authors.affiliation: Department of Chemistry and Australian Cataract Research Foundation, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takikawa
authors.affiliation: Institute for Medical Microbiology and Virology, Heinrich-Heine University, Universitätsstraße 1, 40225 Düsseldorf, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: DÄubener
mesh_terms: D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial / Q000235:genetics; D016983:Enterococcus / Q000187:drug effects / Q000254:growth & development*; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology*; D007737:Kynurenine / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D014364:Tryptophan / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000378:metabolism*; D019459:Urothelium / Q000187:drug effects* / Q000201:enzymology* / Q000382:microbiology
chemical_list: D017077:Culture Media, Conditioned; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase