The Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model

ABSTRACT Clostridium perfringens type A is involved in gas gangrene in humans and animals. Following a traumatic injury, rapid bacterial proliferation and exotoxin production result in severe myonecrosis. C. perfringens alpha toxin (CPA) and perfringolysin (PFO) are the main virulence factors respon...

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Autores principales:	Mauricio A. Navarro, Jihong Li, Juliann Beingesser, Bruce A. McClane, Francisco A. Uzal
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Clostridium perfringens Agr-like quorum-sensing system gas gangrene Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d2135dc2b1984eb49ba716bdbefe07e4
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spelling	oai:doaj.org-article:d2135dc2b1984eb49ba716bdbefe07e42021-11-15T15:30:14ZThe Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model10.1128/mSphere.00500-202379-5042https://doaj.org/article/d2135dc2b1984eb49ba716bdbefe07e42020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00500-20https://doaj.org/toc/2379-5042ABSTRACT Clostridium perfringens type A is involved in gas gangrene in humans and animals. Following a traumatic injury, rapid bacterial proliferation and exotoxin production result in severe myonecrosis. C. perfringens alpha toxin (CPA) and perfringolysin (PFO) are the main virulence factors responsible for the disease. Recent in vitro studies have identified an Agr-like quorum-sensing (QS) system in C. perfringens that regulates the production of both toxins. The system is composed of an AgrB membrane transporter and an AgrD peptide that interacts with a two-component regulatory system in response to fluctuations in the cell population density. In addition, a synthetic peptide named 6-R has been shown to interfere with this signaling mechanism, affecting the function of the Agr-like QS system in vitro. In the present study, C. perfringens type A strain ATCC 3624 and an isogenic agrB-null mutant were tested in a mouse model of gas gangrene. When mice were intramuscularly challenged with 106 CFU of wild-type ATCC 3624, severe myonecrosis and leukocyte aggregation occurred by 4 h. Similar numbers of an agrB-null mutant strain produced significantly less severe changes in the skeletal muscle of challenged mice. Complementation of the mutant to regain agrB expression restored virulence to wild-type levels. The burdens of all three C. perfringens strains in infected muscle were similar. In addition, animals injected intramuscularly with wild-type ATCC 3624 coincubated with the 6-R peptide developed less severe microscopic changes. This study provides the first in vivo evidence that the Agr-like QS system is important for C. perfringens type A-mediated gas gangrene. IMPORTANCE Clostridium perfringens type A strains produce toxins that are responsible for clostridial myonecrosis, also known as gas gangrene. Toxin production is regulated by an Agr-like quorum-sensing (QS) system that responds to changes in cell population density. In this study, we investigated the importance of this QS system in a mouse model of gas gangrene. Mice challenged with a C. perfringens strain with a nonfunctional regulatory system developed less severe changes in the injected skeletal muscle compared to animals receiving the wild-type strain. In addition, a synthetic peptide was able to decrease the effects of the QS in this disease model. These studies provide new understanding of the pathogenesis of gas gangrene and identified a potential therapeutic target to prevent the disease.Mauricio A. NavarroJihong LiJuliann BeingesserBruce A. McClaneFrancisco A. UzalAmerican Society for MicrobiologyarticleClostridium perfringensAgr-like quorum-sensing systemgas gangreneMicrobiologyQR1-502ENmSphere, Vol 5, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium perfringens Agr-like quorum-sensing system gas gangrene Microbiology QR1-502
spellingShingle	Clostridium perfringens Agr-like quorum-sensing system gas gangrene Microbiology QR1-502 Mauricio A. Navarro Jihong Li Juliann Beingesser Bruce A. McClane Francisco A. Uzal The Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model
description	ABSTRACT Clostridium perfringens type A is involved in gas gangrene in humans and animals. Following a traumatic injury, rapid bacterial proliferation and exotoxin production result in severe myonecrosis. C. perfringens alpha toxin (CPA) and perfringolysin (PFO) are the main virulence factors responsible for the disease. Recent in vitro studies have identified an Agr-like quorum-sensing (QS) system in C. perfringens that regulates the production of both toxins. The system is composed of an AgrB membrane transporter and an AgrD peptide that interacts with a two-component regulatory system in response to fluctuations in the cell population density. In addition, a synthetic peptide named 6-R has been shown to interfere with this signaling mechanism, affecting the function of the Agr-like QS system in vitro. In the present study, C. perfringens type A strain ATCC 3624 and an isogenic agrB-null mutant were tested in a mouse model of gas gangrene. When mice were intramuscularly challenged with 106 CFU of wild-type ATCC 3624, severe myonecrosis and leukocyte aggregation occurred by 4 h. Similar numbers of an agrB-null mutant strain produced significantly less severe changes in the skeletal muscle of challenged mice. Complementation of the mutant to regain agrB expression restored virulence to wild-type levels. The burdens of all three C. perfringens strains in infected muscle were similar. In addition, animals injected intramuscularly with wild-type ATCC 3624 coincubated with the 6-R peptide developed less severe microscopic changes. This study provides the first in vivo evidence that the Agr-like QS system is important for C. perfringens type A-mediated gas gangrene. IMPORTANCE Clostridium perfringens type A strains produce toxins that are responsible for clostridial myonecrosis, also known as gas gangrene. Toxin production is regulated by an Agr-like quorum-sensing (QS) system that responds to changes in cell population density. In this study, we investigated the importance of this QS system in a mouse model of gas gangrene. Mice challenged with a C. perfringens strain with a nonfunctional regulatory system developed less severe changes in the injected skeletal muscle compared to animals receiving the wild-type strain. In addition, a synthetic peptide was able to decrease the effects of the QS in this disease model. These studies provide new understanding of the pathogenesis of gas gangrene and identified a potential therapeutic target to prevent the disease.
format	article
author	Mauricio A. Navarro Jihong Li Juliann Beingesser Bruce A. McClane Francisco A. Uzal
author_facet	Mauricio A. Navarro Jihong Li Juliann Beingesser Bruce A. McClane Francisco A. Uzal
author_sort	Mauricio A. Navarro
title	The Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model
title_short	The Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model
title_full	The Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model
title_fullStr	The Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model
title_full_unstemmed	The Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model
title_sort	agr-like quorum-sensing system is important for <italic toggle="yes">clostridium perfringens</italic> type a strain atcc 3624 to cause gas gangrene in a mouse model
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/d2135dc2b1984eb49ba716bdbefe07e4
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The Agr-Like Quorum-Sensing System Is Important for <italic toggle="yes">Clostridium perfringens</italic> Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model

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