Enterococcus faecalis Overcomes Foreign Body-Mediated Inflammation To Establish Urinary Tract Infections

Abstract

Urinary catheterization elicits major histological and immunological changes that render the bladder susceptible to microbial invasion, colonization, and dissemination. However, it is not understood how catheters induce these changes, how these changes act to promote infection, or whether they may have any protective benefit. In the present study, we examined how catheter-associated inflammation impacts infection by Enterococcus faecalis, a leading cause of catheter-associated urinary tract infection (CAUTI), a source of significant societal and clinical challenges. Using a recently optimized murine model of foreign body-associated UTI, we found that the implanted catheter itself was the primary inducer of inflammation. In the absence of the silicone tubing implant, E. faecalis induced only minimal inflammation and was rapidly cleared from the bladder. The catheter-induced inflammation was only minimally altered by subsequent enterococcal infection and was not suppressed by inhibitors of the neurogenic pathway and only partially by dexamethasone. Despite the robust inflammatory response induced by urinary implantation, E. faecalis produced biofilm and high bladder titers in these animals. Induction of inflammation in the absence of an implanted catheter failed to promote infection, suggesting that the presence of the catheter itself is essential for E. faecalis persistence in the bladder. Immunosuppression prior to urinary catheterization enhanced E. faecalis colonization, suggesting that implant-mediated inflammation contributes to the control of enterococcal infection. Thus, this study underscores the need for novel strategies against CAUTIs that seek to reduce the deleterious effects of implant-mediated inflammation on bladder homeostasis while maintaining an active immune response that effectively limits bacterial invaders. U rinary catheterization is directly associated with 80% of hospital-acquired urinary tract infections (UTIs) (1). The insertion and presence of indwelling urinary catheters disrupt the normal mechanical and host defenses of the urinary tract, allow extracellular microbes access to the sterile environment of the bladder by ascending through the catheter lumen or from the urethral meatus along the catheter, and provide an additional surface for biofilm formation and the establishment of antibioticrecalcitrant chronic or recurrent infections (2-9). Even in the absence of microbial colonization, urinary catheterization was shown to be associated with histological and immunological alterations in the bladder, including urothelial damage and exfoliation, bladder wall edema, inflammatory cytokine production, immune cell infiltration, and mucosal lesions of the bladders and kidneys (7, 10-13) which can lead to bladder cancers (14, 15). However, there remains a need to uncover molecular details and the functional role of the catheter-induced host responses during bacterial colonization and catheter-associated UTIs (CAUTIs).We recently optimized a murine model of foreign body-associated UTI to inv...

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

“…Catheterization has been shown to induce a strong, localized inflammatory response that results in tissue damage and edema (26,37,38). Bladder inflammation in this model, measured via a change in bladder weight (37), was significantly increased in mock-infected implanted mice compared with naïve, as expected (naïve vs. PBS-I, 6 h; Fig. 3A).…”

“…Additionally, both pathogens exacerbate the implant-induced inflammation by up-regulating additional cytokines known to signal neutrophil activation or recruitment, including IL-17, IL1-β, granulocyte colony-stimulating factor, and keratinocyte-derived chemokine (58)(59)(60) and, during E. faecalis infection, correlated with increased numbers of activated neutrophils within the implanted bladder (37). Additionally, both pathogens up-regulate expression of IL-6 following infection above the levels induced by the implant alone (37). E. faecalis also exploits the presence of Fg to form biofilm on catheter implants during CAUTI (26).…”

“…This results in the up-regulation of virulence factors essential for survival and dissemination (34,35). The findings that urinary catheterization alters the UT environment by triggering the release of Fg (26) and that MRSA UTI is predominately associated with urinary catheterization (26,(36)(37)(38) suggest that MRSA may exploit the presence of this host protein to cause disease. Additionally, this process is known to be true for Enterococcus faecalis, which expresses an endocarditis-and biofilm-associated (Ebp) pilus that is tipped with the Fg-binding protein EbpA.…”

“…Our previous reports show that E. faecalis shares several common features with MRSA during CAUTI (26,(36)(37)(38)57). First, both E. faecalis and MRSA cause persistent disease by overcoming the inflammation induced upon implant placement, which consists of the recruitment of immune cells, including activated macrophages and neutrophils (37).…”

“…First, both E. faecalis and MRSA cause persistent disease by overcoming the inflammation induced upon implant placement, which consists of the recruitment of immune cells, including activated macrophages and neutrophils (37). Additionally, both pathogens exacerbate the implant-induced inflammation by up-regulating additional cytokines known to signal neutrophil activation or recruitment, including IL-17, IL1-β, granulocyte colony-stimulating factor, and keratinocyte-derived chemokine (58)(59)(60) and, during E. faecalis infection, correlated with increased numbers of activated neutrophils within the implanted bladder (37). Additionally, both pathogens up-regulate expression of IL-6 following infection above the levels induced by the implant alone (37).…”