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 heteropolyme...

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Autores principales:	Ana L. Flores-Mireles, Jennifer N. Walker, Aaron Potretzke, Henry L. Schreiber, Jerome S. Pinkner, Tyler M. Bauman, Alyssa M. Park, Alana Desai, Scott J. Hultgren, Michael G. Caparon
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d810f3b372fb46a8a5589b9b53df6a7c
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spelling	oai:doaj.org-article:d810f3b372fb46a8a5589b9b53df6a7c2021-11-15T15:50:15ZAntibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections10.1128/mBio.01653-162150-7511https://doaj.org/article/d810f3b372fb46a8a5589b9b53df6a7c2016-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01653-16https://doaj.org/toc/2150-7511ABSTRACT 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 EbpANTD confers 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, EbpANTD antibodies 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. IMPORTANCE 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.Ana L. Flores-MirelesJennifer N. WalkerAaron PotretzkeHenry L. SchreiberJerome S. PinknerTyler M. BaumanAlyssa M. ParkAlana DesaiScott J. HultgrenMichael G. CaparonAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Ana L. Flores-Mireles Jennifer N. Walker Aaron Potretzke Henry L. Schreiber Jerome S. Pinkner Tyler M. Bauman Alyssa M. Park Alana Desai Scott J. Hultgren Michael G. Caparon Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections
description	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 EbpANTD confers 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, EbpANTD antibodies 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. IMPORTANCE 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.
format	article
author	Ana L. Flores-Mireles Jennifer N. Walker Aaron Potretzke Henry L. Schreiber Jerome S. Pinkner Tyler M. Bauman Alyssa M. Park Alana Desai Scott J. Hultgren Michael G. Caparon
author_facet	Ana L. Flores-Mireles Jennifer N. Walker Aaron Potretzke Henry L. Schreiber Jerome S. Pinkner Tyler M. Bauman Alyssa M. Park Alana Desai Scott J. Hultgren Michael G. Caparon
author_sort	Ana L. Flores-Mireles
title	Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections
title_short	Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections
title_full	Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections
title_fullStr	Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections
title_full_unstemmed	Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections
title_sort	antibody-based therapy for enterococcal catheter-associated urinary tract infections
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/d810f3b372fb46a8a5589b9b53df6a7c
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Antibody-Based Therapy for Enterococcal Catheter-Associated Urinary Tract Infections

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