Role of Uropathogenic Escherichia coli Virulence Factors in Development of Urinary Tract Infection and Kidney Damage

Abstract

Uropathogenic Escherichia coli (UPEC) is a causative agent in the vast majority of urinary tract infections (UTIs), including cystitis and pyelonephritis, and infectious complications, which may result in acute renal failure in healthy individuals as well as in renal transplant patients. UPEC expresses a multitude of virulence factors to break the inertia of the mucosal barrier. In response to the breach by UPEC into the normally sterile urinary tract, host inflammatory responses are triggered leading to cytokine production, neutrophil influx, and the exfoliation of infected bladder epithelial cells. Several signaling pathways activated during UPEC infection, including the pathways known to activate the innate immune response, interact with calcium-dependent signaling pathways. Some UPEC isolates, however, might possess strategies to delay or suppress the activation of components of the innate host response in the urinary tract. Studies published in the recent past provide new information regarding how virulence factors of uropathogenic E. coli are involved in activation of the innate host response. Despite numerous host defense mechanisms, UPEC can persist within the urinary tract and may serve as a reservoir for recurrent infections and serious complications. Presentation of the molecular details of these events is essential for development of successful strategies for prevention of human UTIs and urological complications associated with UTIs.

Figure 1

Model of UPEC-induced signaling cascades in urothelial cells. Bacterial adherence to uroepithelium results in an epithelial inflammatory response including local production of chemokines and cytokines or cell death via apoptosis. Activation of TLR4 through virulence factors, including LPS and fimbriae, triggers the response, which involves activation of kinases and subsequent translocation of different transcriptional factors such as NF-κB, CREB, and IFR3 into the nucleus. HlyA (through LPS-LBP-CD14 complex) is delivered to the cell membrane and activates there GTPase RhoA, which is required for Ca²⁺ signaling. Specific HlyA-induced Ca²⁺ oscillations lead to activation of NF-κB and synthesis of IL6/IL-8. Chemokine production leads to recruitment of neutrophils that kill the bacteria by producing the cytotoxic substances. Tissue damage, cell death, and permanent scarring result in excessive inflammatory response.