title: Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections.
abstract: Gram-positive bacteria in the genus Enterococcus are a frequent cause of catheter-associated urinary tract infection (CAUTI), a disease whose treatment is increasingly challenged by multiantibiotic-resistant strains. We have recently shown that E. faecalis uses the Ebp pilus, a heteropolymeric surface fiber, to bind the host protein fibrinogen as a critical step in CAUTI pathogenesis. Fibrinogen is deposited on catheters due to catheter-induced inflammation and is recognized by the N-terminal domain of EbpA (EbpANTD), the Ebp pilus's adhesin. In a murine model, vaccination with EbpANTDconfers significant protection against CAUTI. Here, we explored the mechanism of protection using passive transfer of immune sera to show that antisera blocking EbpANTD-fibrinogen interactions not only is prophylactic but also can act therapeutically to reduce bacterial titers of an existing infection. Analysis of 55 clinical CAUTI, bloodstream, and gastrointestinal isolates, including E. faecalis, E. faecium, and vancomycin-resistant enterococci (VRE), revealed a diversity of levels of EbpA expression and fibrinogen-binding efficiency in vitro Strikingly, analysis of 10 strains representative of fibrinogen-binding diversity demonstrated that, irrespective of EbpA levels, EbpANTDantibodies were universally protective. The results indicate that, despite diversity in levels of fibrinogen binding, strategies that target the disruption of EbpANTD-fibrinogen interactions have considerable promise for treatment of CAUTI.
  
  
  
  Urinary catheterization is a routine medical procedure, and it has been estimated that 30 million Foley catheters are used annually in the United States. Importantly, placement of a urinary catheter renders the patient susceptible to developing a catheter-associated urinary tract infection, accounting for 1 million cases per year. Additionally, these infections can lead to serious complications, including bloodstream infection and death. Enterococcus strains are a common cause of these infections, and management of enterococcal infections has been more difficult in recent years due to the development of antibiotic resistance and the ability of strains to disseminate, resulting in a major threat in hospital settings. In this study, we developed an antibiotic-sparing treatment that is effective against diverse enterococcal isolates, including vancomycin-resistant enterococci, during catheter-associated urinary tract infections.
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors: Ana L
authors: AL
authors: Flores-Mireles
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors: Jennifer N
authors: JN
authors: Walker
authors: Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors: Aaron
authors: A
authors: Potretzke
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors: Henry L
authors: HL
authors: Schreiber
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors: Jerome S
authors: JS
authors: Pinkner
authors: Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors: Tyler M
authors: TM
authors: Bauman
authors: Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors: Alyssa M
authors: AM
authors: Park
authors: Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors: Alana
authors: A
authors: Desai
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, Missouri, USA hultgren@wustl.edu caparon@wustl.edu.
authors: Scott J
authors: SJ
authors: Hultgren
authors: Department of Molecular Microbiology and Center for Women's Infectious Disease Research, Washington University School of Medicine, Saint Louis, Missouri, USA hultgren@wustl.edu caparon@wustl.edu.
authors: Michael G
authors: MG
authors: Caparon
mesh_terms: D018829:Adhesins, Bacterial / Q000276:immunology; D000818:Animals; D000907:Antibodies, Bacterial / Q000008:administration & dosage*; D055499:Catheter-Related Infections / Q000517:prevention & control / Q000628:therapy*; D004195:Disease Models, Animal; D016983:Enterococcus / Q000276:immunology* / Q000302:isolation & purification; D016908:Gram-Positive Bacterial Infections / Q000517:prevention & control / Q000628:therapy*; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D007167:Immunotherapy / Q000379:methods*; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome; D014481:United States; D014552:Urinary Tract Infections / Q000517:prevention & control / Q000628:therapy*
chemical_list: D018829:Adhesins, Bacterial; D000907:Antibodies, Bacterial