California Animal Health and Food Safety Laboratory System, School of Veterinary Medicine, University of California, Davis, San Bernardino, California, USA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
mSphere. 2020 Jun 17;5(3):e00500-20. doi: 10.1128/mSphere.00500-20.
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.
A 型与人和动物的气性坏疽有关。在创伤后，细菌迅速增殖并产生外毒素，导致严重的肌肉坏死。α毒素（CPA）和产气荚膜梭菌（PFO）是导致该病的主要毒力因子。最近的研究发现，该菌中存在一种 Agr 样群体感应（QS）系统，该系统调节两种毒素的产生。该系统由 AgrB 膜转运蛋白和 AgrD 肽组成，可与双组分调控系统相互作用，以响应细胞群体密度的波动。此外，一种名为 6-R 的合成肽已被证明可干扰这种信号转导机制，影响 Agr 样 QS 系统的功能。在本研究中，我们在气性坏疽的小鼠模型中检测了 A 型菌株 ATCC 3624 和一个同源缺失突变株。当用 10 CFU 的野生型 ATCC 3624 肌肉内攻击小鼠时，在 4 小时内会发生严重的肌肉坏死和白细胞聚集。类似数量的缺失突变株在受挑战的小鼠骨骼肌中产生的变化明显较轻。突变株的回补恢复了表达，使毒力恢复到野生型水平。三种菌株在感染肌肉中的负荷相似。此外，肌肉内注射野生型 ATCC 3624 并与 6-R 肽共孵育的动物发展出较轻的显微镜下变化。这项研究首次提供了证据，证明 Agr 样 QS 系统对 A 型介导的气性坏疽很重要。A 型产生的毒素可导致梭状芽胞杆菌性肌坏死，也称为气性坏疽。毒素的产生受 Agr 样群体感应（QS）系统的调控，该系统对细胞群体密度的变化做出反应。在这项研究中，我们在气性坏疽的小鼠模型中研究了该 QS 系统的重要性。与接受野生型菌株的动物相比，接受无功能调控系统的菌株攻击的小鼠，其注射骨骼肌中的变化较轻。此外，一种合成肽能够降低该疾病模型中 QS 的作用。这些研究为气性坏疽的发病机制提供了新的认识，并确定了预防该病的潜在治疗靶点。
