Growth inhibition of multiresistant enterococci by interferon-γ-activated human uro-epithelial cells

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-γ (IFN-γ) inhibited growth of group B streptococci by depleting the essential amino acid L-tryptophan. This study describes the IFN-γ-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-γ-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.