The Agr-Like Quorum-Sensing System Is Important for Type A Strain ATCC 3624 To Cause Gas Gangrene in a Mouse Model.

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. alpha toxin (CPA) and perfringolysin (PFO) are the main virulence factors responsible for the disease. Recent studies have identified an Agr-like quorum-sensing (QS) system in 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 the present study, type A strain ATCC 3624 and an isogenic -null mutant were tested in a mouse model of gas gangrene. When mice were intramuscularly challenged with 10 CFU of wild-type ATCC 3624, severe myonecrosis and leukocyte aggregation occurred by 4 h. Similar numbers of an -null mutant strain produced significantly less severe changes in the skeletal muscle of challenged mice. Complementation of the mutant to regain expression restored virulence to wild-type levels. The burdens of all three 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 evidence that the Agr-like QS system is important for type A-mediated gas gangrene. 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 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.