Our mouse model demonstrated catheter implantation was required for the development of persistent MRSA UTI13. Additionally, we found MRSA infection exacerbated the inflammatory response induced by catheter implants, which we previously showed disrupted the bladder epithelium via mechanical damage, leading to the release of the host protein fibrinogen into the bladder13, 14. This increased inflammatory response differs from what has been reported for Enterococcus faecalis, another catheter-associated uropathogen, which induced a targeted response that specifically stimulated additional fibrinogen release over catheterization alone, suggesting these pathogens may have different virulence mechanisms for causing UTI. The exacerbated immune activation during MRSA CAUTI corresponded with abscess formation, as well as increased accumulation of fibrinogen in the bladder and on the catheter implants13. While fibrinogen is an essential part of the normal healing process required for wound repair15, we found that MRSA exploited its presence via interactions with the clumping factor B adhesin to establish a persistent infection13. Importantly, analysis of urinary catheters from patients with S. aureus positive urine or catheter cultures supported the findings from our mouse model and demonstrated that host factors, including fibrinogen, immune cells, and epithelial cells, were also deposited on human urinary catheters and S. aureus formed biofilm-like communities in patterns that co-localized with host fibrinogen on these catheters13. The mouse model also replicated other aspects of MRSA CAUTI reported in the clinic, including rapid dissemination to bacteremia. Together, this work clarified why S. aureus UTI was strongly associated with urinary catheterization, as the deposition of host factors, including fibrinogen, on urinary catheters altered the bladder habitat, thus increasing susceptibility to the atypical uropathogen, which encoded factors capable of exploiting the host protein.
The discovery that host factors deposited on urinary catheters can facilitate infection has important implications in the field, as it provides a potential pathogenic mechanism for catheter-associated microbes that encode factors capable of exploiting fibrinogen, including MRSA, Enterococcus sps, and Candida sps16. Additionally, this work may provide insights into why antimicrobial-impregnated catheters display inconsistent efficacy in preventing CAUTI during clinical studies3, as the coating of these catheters with human proteins may provide additional ligands for attachment and thus create a physical barrier between the uropathogen and the antimicrobial, limiting its efficacy. Importantly, understanding the mechanisms that lead to CAUTI may provide insights into the development of targeted therapies that block these host-pathogen interactions to effectively limit disease. The need for new and/or alternative therapies is highlighted by recent epidemiologic studies that suggest even appropriate antibiotic treatment of CAUTI may not improve patient outcomes in certain patient populations, such as the elderly and those with recent hospital or long-term care facility exposures2. Furthermore, current guidelines recommend not testing for or treating asymptomatic bacteriuria in catheterized patients, as evidence suggests even appropriate antibiotic treatment does not eradicate catheter-associated biofilms and may actually contribute to adverse events, such as the development of Clostridium difficile colitis, or facilitate the emergence of antimicrobial resistance1. Analysis of patient catheters from our study supports the findings that antibiotics may not be effective at eradicating or preventing S. aureus catheter-associated biofilm, as S. aureus biofilm-like communities were detected on collected urinary catheters despite patients receiving extensive antibiotic therapy specific for S. aureus and/or MRSA13. Challengingly, recent animal studies suggest that production of S. aureus superantigen toxins, which induce a potent activation of the immune system and result in severe morbidity during invasive infections, can also induce a systemic inflammatory response during a localized foreign body infection even without evidence of concomitant bacteremia or dissemination17. These data may clarify why patients with S. aureus bacteriuria often exhibit symptoms more indicative of systemic disease as opposed to those typically associated with symptomatic UTI10, 12. This is particularly concerning as it may have clinical consequences for S. aureus catheter colonization and highlights the importance of implementing proper catheter management strategies, particularly those that strongly reinforce reducing the inappropriate use, prompt removal, or exchange of urinary catheters1-3. Future studies elucidating the host-pathogen mechanisms that contribute to CAUTI may provide insights into the development of effective therapies, as well as allow us to establish better guidelines for the surveillance, prevention, and treatment of symptomatic and asymptomatic bacteriuria, improving the quality of patient care.
Jennifer N Walker, PhD; Michael G. Caparon, PhD; and Scott J. Hultgren PhD, Washington University School of Medicine
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