Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>

ABSTRACT Clostridium difficile infection (CDI) is responsible for most of the definable cases of antibiotic- and hospital-associated diarrhea worldwide and is a frequent cause of morbidity and mortality in older patients. C. difficile, a multidrug-resistant anaerobic pathogen, causes disease by prod...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Charles Darkoh, Chioma Odo, Herbert L. DuPont
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7407f7bf20e441e1a384da15c42af81a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7407f7bf20e441e1a384da15c42af81a
record_format	dspace
spelling	oai:doaj.org-article:7407f7bf20e441e1a384da15c42af81a2021-11-15T15:50:19ZAccessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>10.1128/mBio.01237-162150-7511https://doaj.org/article/7407f7bf20e441e1a384da15c42af81a2016-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01237-16https://doaj.org/toc/2150-7511ABSTRACT Clostridium difficile infection (CDI) is responsible for most of the definable cases of antibiotic- and hospital-associated diarrhea worldwide and is a frequent cause of morbidity and mortality in older patients. C. difficile, a multidrug-resistant anaerobic pathogen, causes disease by producing toxins A and B, which are controlled by an accessory gene regulator (Agr) quorum signaling system. Some C. difficile strains encode two Agr loci in their genomes, designated agr1 and agr2. The agr1 locus is present in all of the C. difficile strains sequenced to date, whereas the agr2 locus is present in a few strains. The functional roles of agr1 and agr2 in C. difficile toxin regulation and pathogenesis were unknown until now. Using allelic exchange, we deleted components of both agr loci and examined the mutants for toxin production and virulence. The results showed that the agr1 mutant cannot produce toxins A and B; toxin production can be restored by complementation with wild-type agr1. Furthermore, the agr1 mutant is able to colonize but unable to cause disease in a murine CDI model. These findings have profound implications for CDI treatment because we have uncovered a promising therapeutic target for the development of nonantibiotic drugs to treat this life-threatening emerging pathogen by targeting the toxins directly responsible for disease. IMPORTANCE Within the last decade, the number of cases of C. difficile infections has been increasing exponentially in the United States, resulting in about 4.8 billion U.S. dollars in health care costs annually. As a multidrug-resistant, spore-forming, anaerobic pathogen, C. difficile overpopulates the colon after the gut microbiota has been altered by antibiotic therapy. With increasing resistance to antibiotic treatment of C. difficile infections, patients are experiencing higher costs of health care and a lower quality of life as treatment options decrease. During infection, C. difficile produces toxins A and B, which directly cause disease. As a result, the toxins have become promising nonantibiotic treatment targets. Here, we have identified a pathway responsible for activating the production of the toxins. This important finding opens up a unique therapeutic target for the development of a novel nonantibiotic therapy for C. difficile infections.Charles DarkohChioma OdoHerbert L. DuPontAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 4 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Charles Darkoh Chioma Odo Herbert L. DuPont Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>
description	ABSTRACT Clostridium difficile infection (CDI) is responsible for most of the definable cases of antibiotic- and hospital-associated diarrhea worldwide and is a frequent cause of morbidity and mortality in older patients. C. difficile, a multidrug-resistant anaerobic pathogen, causes disease by producing toxins A and B, which are controlled by an accessory gene regulator (Agr) quorum signaling system. Some C. difficile strains encode two Agr loci in their genomes, designated agr1 and agr2. The agr1 locus is present in all of the C. difficile strains sequenced to date, whereas the agr2 locus is present in a few strains. The functional roles of agr1 and agr2 in C. difficile toxin regulation and pathogenesis were unknown until now. Using allelic exchange, we deleted components of both agr loci and examined the mutants for toxin production and virulence. The results showed that the agr1 mutant cannot produce toxins A and B; toxin production can be restored by complementation with wild-type agr1. Furthermore, the agr1 mutant is able to colonize but unable to cause disease in a murine CDI model. These findings have profound implications for CDI treatment because we have uncovered a promising therapeutic target for the development of nonantibiotic drugs to treat this life-threatening emerging pathogen by targeting the toxins directly responsible for disease. IMPORTANCE Within the last decade, the number of cases of C. difficile infections has been increasing exponentially in the United States, resulting in about 4.8 billion U.S. dollars in health care costs annually. As a multidrug-resistant, spore-forming, anaerobic pathogen, C. difficile overpopulates the colon after the gut microbiota has been altered by antibiotic therapy. With increasing resistance to antibiotic treatment of C. difficile infections, patients are experiencing higher costs of health care and a lower quality of life as treatment options decrease. During infection, C. difficile produces toxins A and B, which directly cause disease. As a result, the toxins have become promising nonantibiotic treatment targets. Here, we have identified a pathway responsible for activating the production of the toxins. This important finding opens up a unique therapeutic target for the development of a novel nonantibiotic therapy for C. difficile infections.
format	article
author	Charles Darkoh Chioma Odo Herbert L. DuPont
author_facet	Charles Darkoh Chioma Odo Herbert L. DuPont
author_sort	Charles Darkoh
title	Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>
title_short	Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>
title_full	Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>
title_fullStr	Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>
title_full_unstemmed	Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>
title_sort	accessory gene regulator-1 locus is essential for virulence and pathogenesis of <named-content content-type="genus-species">clostridium difficile</named-content>
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/7407f7bf20e441e1a384da15c42af81a
work_keys_str_mv	AT charlesdarkoh accessorygeneregulator1locusisessentialforvirulenceandpathogenesisofnamedcontentcontenttypegenusspeciesclostridiumdifficilenamedcontent AT chiomaodo accessorygeneregulator1locusisessentialforvirulenceandpathogenesisofnamedcontentcontenttypegenusspeciesclostridiumdifficilenamedcontent AT herbertldupont accessorygeneregulator1locusisessentialforvirulenceandpathogenesisofnamedcontentcontenttypegenusspeciesclostridiumdifficilenamedcontent
_version_	1718427406089322496

Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis of <named-content content-type="genus-species">Clostridium difficile</named-content>

Ejemplares similares