Perfringolysin O: The Underrated Clostridium perfringens Toxin?

Verherstraeten, Stefanie; Goossens, Evy; Valgaeren, Bonnie; Pardon, Bart; Timbermont, Leen; Haesebrouck, Freddy; Ducatelle, Richard; Deprez, Piet; Wade, Kristin R.; Tweten, Rodney K.; Immerseel, Filip Van

doi:10.3390/toxins7051702

Cited by 65 publications

(54 citation statements)

References 124 publications

(244 reference statements)

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“…These results suggested that some other bacterial components also contribute to this phenomenon. Perfringolysin O, a cholestrerol-dependent cytolysin, is known as a major toxin produced by C. perfringens type A strains 25 26 . Purified perfringolysin O has been shown to be cytotoxic to polymorphonuclear leukocytes and macrophages 27 28 29 .…”

Section: Discussionmentioning

confidence: 99%

Clostridium perfringens α-Toxin Impairs Innate Immunity via Inhibition of Neutrophil Differentiation

Takehara

Takagishi

Seike

et al. 2016

Sci Rep

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Although granulopoiesis is accelerated to suppress bacteria during infection, some bacteria can still cause life-threatening infections, but the mechanism behind this remains unclear. In this study, we found that mature neutrophils in bone marrow cells (BMCs) were decreased in C. perfringens-infected mice and also after injection of virulence factor α-toxin. C. perfringens infection interfered with the replenishment of mature neutrophils in the peripheral circulation and the accumulation of neutrophils at C. perfringens-infected sites in an α-toxin-dependent manner. Measurements of bacterial colony-forming units in C. perfringens-infected muscle revealed that α-toxin inhibited a reduction in the load of C. perfringens. In vitro treatment of isolated BMCs with α-toxin (phospholipase C) revealed that α-toxin directly decreased mature neutrophils. α-Toxin did not influence the viability of isolated mature neutrophils, while simultaneous treatment of BMCs with granulocyte colony-stimulating factor attenuated the reduction of mature neutrophils by α-toxin. Together, our results illustrate that impairment of the innate immune system by the inhibition of neutrophil differentiation is crucial for the pathogenesis of C. perfringens to promote disease to a life-threatening infection, which provides new insight to understand how pathogenic bacteria evade the host immune system.

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Section: Discussionmentioning

confidence: 99%

Clostridium perfringens α-Toxin Impairs Innate Immunity via Inhibition of Neutrophil Differentiation

Takehara

Takagishi

Seike

et al. 2016

Sci Rep

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“…Studies have indicated that CPA plays an essential role in gas gangrene through the use of cpa mutants, which display demonstrably reduced virulence in a mouse model (Awad et al, 1995). PFO, encoded by the pfoA gene, is identified as a lethal pore-forming cholesterol-dependent cytolysin (CDC) produced by nearly all C. perfringens strains (Verherstraeten et al, 2015). PFO can bind to cholesterolcontaining membranes and oligomerize into a pore complex to lyse cells (Stevens and Bryant, 2002).…”

Section: Introductionmentioning

confidence: 99%

Amentoflavone Attenuates Clostridium perfringens Gas Gangrene by Targeting Alpha-Toxin and Perfringolysin O

et al. 2020

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Clostridium perfringens (C. perfringens) type A strains are the main cause of gas gangrene in humans and animals. Treatment of this lethal disease is limited, and the prognosis is not good. Alpha-toxin (CPA) and perfringolysin O (PFO) secreted by C. perfringens play irreplaceable roles in cytotoxicity to host cells, persistence in host tissues, and lethality of gas gangrene pathology. This work determined the influence of amentoflavone, a biflavonoid isolated from Selaginella tamariscina and other plants, on hemolysis and cytotoxicity mediated by CPA and PFO and evaluated the in vivo therapeutic effect on gas gangrene. Our data showed that amentoflavone could block the hemolysis and cytotoxicity induced by CPA and PFO in vitro, thereby mediating significant protection against mortality of infected mice in a mouse gas gangrene model, efficient bacterial clearance in tissues and alleviation of histological damage in vivo. Based on the above results, amentoflavone may be a potential candidate against C. perfringens infection by reducing CPA and PFO-mediated virulence.

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“…3A). The three candidates that exhibited the highest reduction in spheroid size were azurin (28), theta-toxin (29), and hemolysin E (30). The former is a proapoptotic protein, whereas the latter two are pore-forming toxins, of which theta-toxin has not yet been studied as an engineered bacterial therapeutic to our knowledge.…”

Section: Establishing a Stable Bacteria Co-culture System In Multicelmentioning

confidence: 99%

Rapid screening of engineered microbial therapies in a 3D multicellular model

Harimoto

Singer

Velazquez

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic biology is transforming therapeutic paradigms by engineering living cells and microbes to intelligently sense and respond to diseases including inflammation, infections, metabolic disorders, and cancer. However, the ability to rapidly engineer new therapies far outpaces the throughput of animal-based testing regimes, creating a major bottleneck for clinical translation. In vitro approaches to address this challenge have been limited in scalability and broad applicability. Here, we present a bacteria-in-spheroid coculture (BSCC) platform that simultaneously tests host species, therapeutic payloads, and synthetic gene circuits of engineered bacteria within multicellular spheroids over a timescale of weeks. Long-term monitoring of bacterial dynamics and disease progression enables quantitative comparison of critical therapeutic parameters such as efficacy and biocontainment. Specifically, we screen Salmonella typhimurium strains expressing and delivering a library of antitumor therapeutic molecules via several synthetic gene circuits. We identify candidates exhibiting significant tumor reduction and demonstrate high similarity in their efficacies, using a syngeneic mouse model. Last, we show that our platform can be expanded to dynamically profile diverse microbial species including Listeria monocytogenes, Proteus mirabilis, and Escherichia coli in various host cell types. This high-throughput framework may serve to accelerate synthetic biology for clinical applications and for understanding the host–microbe interactions in disease sites.

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Perfringolysin O: The Underrated Clostridium perfringens Toxin?

Cited by 65 publications

References 124 publications

Clostridium perfringens α-Toxin Impairs Innate Immunity via Inhibition of Neutrophil Differentiation

Clostridium perfringens α-Toxin Impairs Innate Immunity via Inhibition of Neutrophil Differentiation

Amentoflavone Attenuates Clostridium perfringens Gas Gangrene by Targeting Alpha-Toxin and Perfringolysin O

Rapid screening of engineered microbial therapies in a 3D multicellular model

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