Modulation of Host Innate Immune Response in the Bladder by UropathogenicEscherichia coli

Abstract

Uropathogenic Escherichia coli (UPEC), the most frequent cause of urinary tract infection (UTI), is associated with an inflammatory response which includes the induction of cytokine/chemokine secretion by urothelial cells and neutrophil recruitment to the bladder. Recent studies indicate, however, that UPEC can evade the early activation of urothelial innate immune response in vitro. In this study, we report that infection with the prototypic UPEC strain NU14 suppresses tumor necrosis factor alpha (TNF-␣)-mediated interleukin-8 (CXCL-8) and interleukin-6 (CXCL-6) secretion from urothelial cell cultures compared to infection with a type 1 piliated E. coli K-12 strain. Furthermore, examination of a panel of clinical E. coli isolates revealed that 15 of 17 strains also possessed the ability to suppress cytokine secretion. In a murine model of UTI, NU14 infection resulted in diminished levels of mRNAs encoding keratinocyte-derived chemokine, macrophage inflammatory peptide 2, and CXCL-6 in the bladder relative to infection with an E. coli K-12 strain. Furthermore, reduced stimulation of inflammatory chemokine production during NU14 infection correlated with decreased levels of bladder and urine myeloperoxidase and increased bacterial colonization. These data indicate that a broad phylogenetic range of clinical E. coli isolates, including UPEC, may evade the activation of innate immune response in the urinary tract, thereby providing a pathogenic advantage.Urinary tract infections (UTI) are most frequently caused by an ascending colonization of the bladder and/or kidneys by Escherichia coli (9, 33). Infection of the urinary tract results in an inflammatory response characterized by increased levels of urinary cytokines and neutrophil influx (1, 13-15). The innate immune response to infection by uropathogenic E. coli (UPEC) depends upon activation of host pattern recognition receptors of the Toll-like receptor pathway, including Toll-like receptor 4 (TLR4) (5,16,(37)(38)(39). Recognition of E. coli lipopolysaccharide (LPS) by urothelial cells that express TLR4 results in activation of the proinflammatory and prosurvival NF-B pathway and secretion of chemokines/cytokines, including CXCL-6 and CXCL-8 (2). The resulting accumulation of inflammatory chemokines in the bladder mucosa and urine during UTI induces the recruitment of neutrophils, which leads to the clearance of bacteria and resolution of infection. Infection of the urinary tract by UPEC also induces adaptive immune responses characterized by humoral and cell-mediated responses which protect against future infection (42).Many pathogenic bacterial species possess the ability to modulate the innate immune response to evade host defenses and promote colonization, including several that block the activation of the NF-B pathway (7,31,32,35,36). We previously reported that UPEC strain NU14 blocks activation of the NF-B pathway and thereby promotes apoptosis (26,27). Insertional mutation of the genes encoding the periplasmic chaperone SurA or the LPS biosynthetic oper...

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

“…Several studies reported suppression of cytokine production in response to UPEC in vitro infection. 35,64,65 This discrepancy with our results is likely due to differences in post-infection incubation time and is therefore reflecting differences between acute and persistent phase of infection.…”

Escherichia coli colonizing the neurogenic bladder are similar to widespread clones causing disease in patients with normal bladder function

“…The persistence of a 1-2 E. coli clones in the neurogenic bladder may be due to E. coli's growth rate in the urine over other species 18 and/or its ability to evade the host's innate immune response. 19 In addition, phylogenetic group and/or virulence genes may promote selection and persistence of specific clones.…”

Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins

“…During the course of an infection, UPEC can stimulate a number of antimicrobial, proinflammatory, prodifferentiation, proliferation, and host cell death pathways (Mulvey, 2002;Mysorekar et al, 2002). In some cases, UPEC can reportedly modulate these signaling events, causing attenuation of host inflammatory responses and potentiating host apoptotic cascades (Klumpp et al, 2001(Klumpp et al, , 2006Hunstad et al, 2005;Billips et al, 2007). These phenomena have been linked in part to the suppression of nuclear factor-B (NF B) activation and downstream signaling by unknown factors associated with UPEC (Klumpp et al, 2001;Hunstad et al, 2005).…”