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

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of catheter-associated urinary tract infection (CAUTI), which frequently progresses to more serious invasive infections. We adapted a mouse model of CAUTI to investigate how catheterization increases an individual's susceptibility to MRSA UTI. This analysis revealed that catheterization was required for MRSA to achieve high-level, persistent infection in the bladder. As shown previously, catheter placement induced an inflammatory response resulting in the release of the host protein fibrinogen (Fg), which coated the bladder and implant. Following infection, we showed that MRSA attached to the urothelium and implant in patterns that colocalized with deposited Fg. Furthermore, MRSA exacerbated the host inflammatory response to stimulate the additional release and accumulation of Fg in the urinary tract, which facilitated MRSA colonization. Consistent with this model, analysis of catheters from patients with S. aureus-positive cultures revealed colocalization of Fg, which was deposited on the catheter, with S. aureus. Clumping Factors A and B (ClfA and ClfB) have been shown to contribute to MRSA-Fg interactions in other models of disease. We found that mutants in clfA had significantly greater Fg-binding defects than mutants in clfB in several in vitro assays. Paradoxically, only the ClfB − strain was significantly attenuated in the CAUTI model. Together, these data suggest that catheterization alters the urinary tract environment to promote MRSA CAUTI pathogenesis by inducing the release of Fg, which the pathogen enhances to persist in the urinary tract despite the host's robust immune response.host-pathogen interactions | MRSA CAUTI | ClfB-fibrinogen interactions

Cuminaldehyde potentiates the antimicrobial actions of ciprofloxacin against Staphylococcus aureus and Escherichia coli

“…Bacteria such as Escherichia coli and Staphylococcus aureus are important agents of urinary tract infections [1][2][3][4]. Both bacteria are frequently detected in patients with indwelling urinary tract devices [1,[5][6][7]. These primary infections often evolve to severe infectious diseases such as sepsis, which presents high morbidity and mortality.…”

Staphylococcus Aureus Bacteriuria as a Predictor of In-Hospital Mortality in Patients with Staphylococcus Aureus Bacteremia. Results of a Retrospective Cohort Study

“…While certain toxins were shown to play a role in severity of SA-BSI [8], the invasion of host cells and virulence of S. aureus is largely determined by fibronectin binding and it could explain intrarenal translocation into the urinary tract [9]. A recent in-vivo study suggested that urinary tract colonization and infection with MRSA is based on the release of fibrinogen after catheter associated tissue damage in mice and humans [10]. In relation to that, SABU was described as a prognostic factor in the identification of complicated SA-BSI [11], as well as being associated with increased mortality in patients with SA-BSI [12,13].…”

Urinary Catheter Coating Modifications: The Race against Catheter-Associated Infections

“…Another issue arises from the media itself, it was discovered that in mice and humans, urinary catheterization causes physical trauma to the lining of the bladder, inducing an inflammatory response and consequently, changing the bladder environment [66,125,[163][164][165][166]. As part of the inflammatory response, serum proteins are released and accumulated into the bladder and deposited onto the urinary catheter [64][65][66]150,167]. Therefore, urinary catheterization creates a new niche that is often not efficiently mimicked in in vitro studies [157], leading to frustration when promising coating modifications fall short in clinical trials.…”

“…Often, controlled drug delivery systems rely on sustained passive delivery, although this often results in exposure of bacterial pathogens to sub-lethal antimicrobial doses. Additionally, the release of antimicrobial compounds may also be hindered by the deposition of host proteins onto the catheter due to inflammatory response caused by the urinary catheterization [64,65,150,[166][167][168]. All of these together may explain why promising coating technologies in vitro yield mixed results when tested in clinical trials [102].…”

“…By understanding the host response to urinary catheterization and infection, more efficient coating and modifications can be developed. Recently, it was found that one of the host proteins released by the inflammatory response, fibrinogen, is essential for biofilm formation in vivo by several prevalent uropathogens such as enterococcal strains, methicillin-resistant S. aureus, Acinetobacter baumannii, and even the fungal pathogen C. albicans [64,65,150,[166][167][168]. The fact that different groups of pathogens use host proteins for biofilm formation suggests a common pathway for colonization in the catheterized environment.…”