Abstract
Clostridium perfringens (C. perfringens) is Gram-positive anaerobic, spore-forming rod-shaped bacterial pathogen that is widely distributed in nature. This bacterium is known as the causative agent of a foodborne illness and of gas gangrene. While the major virulence factors are the α-toxin and perfringolysin O (PFO) produced by type A strains of C. perfringens, the precise mechanisms of how these toxins induce the development of gas gangrene are still not well understood. In this study, we analyzed the host responses to these toxins, including inflammasome activation, using mouse bone marrow-derived macrophages (BMDMs). Our results demonstrated, for the first time, that C. perfringens triggers the activation of caspase-1 and release of IL-1β through PFO-mediated inflammasome activation via a receptor of the Nod-like receptor (NLR) family, pyrin-domain containing 3 protein (NLRP3). The PFO-mediated inflammasome activation was not induced in the cultured myocytes. We further analyzed the functional roles of the toxins in inducing myonecrosis in a mouse model of gas gangrene. Although the myonecrosis was found to be largely dependent on the α-toxin, PFO also induced myonecrosis to a lesser extent, again through the mediation of NLRP3. These results suggest that C. perfringens triggers inflammatory responses via PFO-mediated inflammasome activation via NLRP3, and that this axis contributes in part to the progression of gas gangrene. Our findings provide a novel insight into the molecular mechanisms underlying the pathogenesis of gas gangrene caused by C. perfringens.
Highlights
Clostridium perfringens is commonly isolated from the environment, and from human and animal intestines as a component of the normal flora (Songer, 1996)
To investigate the inflammasome activation in the host cells directed against C. perfringens infection, LPS-primed mouse bone marrow-derived macrophages (BMDMs) were infected with strain 13, a wild-type (WT) strain of C. perfringens
D, ATCC 13124 induced pyroptosis to the same degree as strain 13, but at a lower multiplicity of infection (MOI) (2.5) as compared to strain 13 (25). These results indicated that C. perfringens infection induces inflammasome activation and pyroptosis, a form of proinflammatory cell death of macrophages, with release of IL-1β
Summary
Clostridium perfringens is commonly isolated from the environment (e.g., soil), and from human and animal intestines as a component of the normal flora (Songer, 1996). C. perfringens has been classified into five groups (types A to E) according to their production of four major toxins, namely, α (CPA), β (CPB), ε (ETX), and ι (ITX) toxin (Uzal et al, 2010). The bacteria can produce up to 16 other toxins in various combinations, including perfringolysin O Inflammasome Activation by Perfringolysin O called θ-toxin), enterotoxin (CPE), and beta toxin (CPB2) (Uzal et al, 2010). Type A C. perfringens is the causative strain for the majority of human infections, including gas gangrene. The α-toxin and PFO produced by the type A strains are the major virulence factors of C. perfringens. The precise mechanisms underlying the toxin-mediated myonecrosis in gas gangrene are still unclear
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