This Article Full Text Full Text (PDF) Other Versions of this Article: IAI.00069-08v1 76/9/3891    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Google Scholar Articles by Billips, B. K. Articles by Klumpp, D. J. PubMed PubMed Citation Articles by Billips, B. K. Articles by Klumpp, D. J.

 Previous Article  |  Next Article 

Infection and Immunity, September 2008, p. 3891-3900, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00069-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Molecular Basis of Uropathogenic Escherichia coli Evasion of the Innate Immune Response in the Bladder

Departments of Urology,¹ Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Tarry 16-703, 303 E. Chicago Avenue, Chicago, Illinois 60611²

Received 17 January 2008/ Returned for modification 20 February 2008/ Accepted 7 June 2008

In the urinary tract, the innate immune system detects conserved bacterial components and responds to infection by activating the proinflammatory transcription factor NF-B, resulting in cytokine secretion and neutrophil recruitment. Uropathogenic Escherichia coli (UPEC), however, has been shown to evade the host innate immune response by suppressing NF-B activation in urothelial cells, which results in decreased cytokine secretion and increased urothelial apoptosis. To understand the molecular basis of UPEC modulation of inflammation, we performed a genetic screen with UPEC strain NU14 to identify genes which are required for modulation of urothelial cytokine secretion. Disruption of ampG (peptidoglycan permease), waaL (lipopolysaccharide O antigen ligase), or alr (alanine racemase) resulted in increased urothelial interleukin-8 (IL-8) and IL-6 release from urothelial cell cultures. Targeted deletion of these genes also resulted in elevated urothelial cytokine production during UPEC infection. Conditioned media from bacterial cultures of NU14 ampG and NU14 waaL contained a heat-stable factor(s) which stimulated greater urothelial IL-8 secretion than that in NU14-conditioned medium. In a mouse model of urinary tract infection, NU14 ampG, NU14 waaL, and NU14 alr were attenuated compared to wild-type NU14 and showed reduced fitness in competition experiments. Instillation of NU14 ampG or NU14 waaL increased bladder neutrophil recruitment, indicating that enhanced urothelial cytokine secretion during urinary tract infection results in an altered host response. Thus, UPEC evasion of innate immune detection of bacterial components, such as lipopolysaccharide and peptidoglycan fragments, is likely an important factor in the ability of UPEC to colonize the urinary tract.

Published ahead of print on 16 June 2008.

Editor: A. J. Bäumler