Urinary Tract InfectionUPEC genomics/geneticsChaperone/Usher Pathway PiliEnterococcal pathogenesis/catheter-associated UTIBacterial amyloid (Curli) biogenesisBacterial Community Interactions (Biofilms and Microbiome)Drug and Vaccine Development

Catheter-associated UTIs (CAUTIs)

CAUTIs are the most common cause of hospital-associated infections (HAIs) in the US. According to the “Association for Professionals in Infection Control and Epidemiology”, >30 million Foley catheters are inserted annually in the United States, contributing to 1 million CAUTIs. Patient catheterization rates in acute care hospitals are estimated to be 10%, and in long-term care facilities estimated to range from 7.5% to 25%. Short-term urinary catheterization increases the risk of developing UTI and other complications up to 80%, and prolonged catheterization can increase the risk to 100%. Additionally, patients with catheter-associated bacteriuria have a 3% risk of bacteremia. While UPEC causes 85% of uncomplicated UTIs and 50% of CAUTI, other pathogens such as Enterococcus, Staphylococcus, Klebsiella and Acinetobacter are more common causes of CAUTI. Thus, given the prevalence and rising antibiotic resistance profiles of CAUTI-associated uropathogens, as well as the effect that catheterization has on the susceptibility to infection, we developed a mouse model of CAUTI, which mimics many of the features of clinical disease. Using this model we have elucidated aspects of E. faecalis CAUTI pathogenesis and demonstrated that EbpA, the adhesin of Ebp, which contains a metal ion-dependent adhesion site (MIDAS), is required for E. faecalis colonization in a catheter-implanted bladder. Further characterization of EbpA binding, along with determination of the pathogenic mechanisms by which E. faecalis causes disease, will aid in the identification of novel therapeutic targets for E. faecalis CAUTI.

Colocalization between E.faecalis and fibrinogen

E. faecalis co-localized with fibrinogen on implanted mouse bladder during CAUTI.
Nuclei in blue, mouse uroplakin III in red, fibrinogen in green and E. faecalis in purple.

We found that urinary catheterization triggers a robust inflammatory response, likely due to mechanical stress and epithelial wounding. Under normal circumstances, fibrinogen (fg) is required to aid in the healing of damaged tissue. However, in CAUTI, we found that fg is released into the bladder and binds to the urinary catheter, providing a ligand for fg-binding uropathogens and thus facilitating bacterial colonization and biofilm formation. Importantly, several common HAI bacterial pathogens, including MRSA and VRE, which have been identified by the CDC as significant and growing threats to human health, have been shown to bind fg to initiate and establish infection. Examination of clinical catheters from patients showed that fg and other host proteins are deposited on indwelling catheters, providing a binding surface for MRSA, E. faecalis, E. coli and a variety of other bacteria, which seldom cause disease in immunocompetent, non-catheterized patients. This may in part explain why catheterized patients are at a higher risk for disease. For CAUTIs we have shown that: i) implanted catheters are a primary inducer of bladder inflammation in mouse models; ii) the amino-terminal domain of the EbpA (EbpANTD) adhesin at the tip of the endocarditis- and biofilm-associated pilus (Ebp) in E. faecalis binds host fibrinogen deposited on catheters implanted in the mouse bladder; iii) antisera blocking EbpANTD-fibrinogen interactions can reduce E. faecalis, E. faecium, and VRE CAUTIs; and iv) urinary catheters from hospitalized patients had fibrinogen deposits to which E. faecalis, Staphylococcus aureus, and Candida albicans were able to bind ex vivo.

We also developed the first model of A. baumannii CAUTI infection. Acinetobacter are difficult to treat and carry plasmids that confer resistance to most common antibiotics such as penicillins, aminoglycosides, cephalosporins, and quinolones. We have shown that A. baumannii is able to establish both implant and bladder colonization and colonization is dependent on CUP pili tipped with the CupD adhesin. We have begun the structural and functional characterization of CupD and a related adhesin, PrpD, which bind to fibrinogen.

Collaborators: Mike Caparon, Mario Feldman