Granulocyte Colony-Stimulating Factor Does Not Influence Clostridium Perfringens α-Toxin-Induced Myonecrosis in Mice.

Masaya Takehara,Hiroto Bandou,Keiko Kobayashi,Yuuta Sonobe,Masahiro Nagahama

doi:10.3390/toxins11090509

Masaya Takehara, Hiroto Bandou + Show 3 more

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https://doi.org/10.3390/toxins11090509

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Journal: Toxins	Publication Date: Aug 30, 2019
Citations: 4	License type: CC BY 4.0

Affiliation: Tokushima Bunri University

Abstract

Clostridium perfringens type A causes gas gangrene characterized by myonecrosis and development of an effective therapy for treating affected patients is of clinical importance. It was recently reported that the expression of granulocyte colony-stimulating factor (G-CSF) is greatly up-regulated by C. perfringens infection. However, the role of G-CSF in C. perfringens-mediated myonecrosis is still unclear. Here, we assessed the destructive changes in C. perfringens-infected skeletal muscles and tested whether inhibition of G-CSF receptor (G-CSFR) signaling or administration of recombinant G-CSF affects the tissue injury. Severe edema, contraction of muscle fiber diameter, and increased plasma creatine kinase activity were observed in mice intramuscularly injected with C. perfringens type A, and the destructive changes were α-toxin-dependent, indicating that infection induces the destruction of skeletal muscle in an α-toxin-dependent manner. G-CSF plays important roles in the protection of tissue against damage and in the regeneration of injured tissue. However, administration of a neutralizing antibody against G-CSFR had no profound impact on the destructive changes to skeletal muscle. Moreover, administration of recombinant human G-CSF, filgrastim, imparted no inhibitory effect against the destructive changes caused by C. perfringens. Together, these results indicate that G-CSF is not beneficial for treating C. perfringens α-toxin-mediated myonecrosis, but highlight the importance of revealing the mechanism by which C. perfringens negates the protective effects of G-CSF in skeletal muscle.

Highlights

Clostridium perfringens type A is a Gram-positive anaerobic bacterium that causes gas gangrene [1,2].The disease is characterized by myonecrosis, shock, multiple organ failure, and death of patients [3].The infection progresses so rapidly that death precedes diagnosis in some patients and, the development of an effective therapy for treating patients with C. perfringens-mediated myonecrosis is of utmost importance.The well-known virulence factors produced by C. perfringens type A are α-toxin, which has both phospholipase C (PLC) and sphingomyelinase (SMase) activities [3,4], and θ-toxin, which is a pore-forming and cholesterol-dependent cytolysin [5,6]
It was previously reported that C. perfringens infection causes myonecrosis in mice and the severity of skeletal muscle necrosis decreased in mice injected with the α-toxin-deficient strain [7]
Plasma creatine kinase activity increased in C. perfringens-infected mice. These results indicate that C. perfringens infection induces the destruction of skeletal muscle

Summary

Introduction

Clostridium perfringens type A is a Gram-positive anaerobic bacterium that causes gas gangrene [1,2].The disease is characterized by myonecrosis, shock, multiple organ failure, and death of patients [3].The infection progresses so rapidly that death precedes diagnosis in some patients and, the development of an effective therapy for treating patients with C. perfringens-mediated myonecrosis is of utmost importance.The well-known virulence factors produced by C. perfringens type A are α-toxin (or phospholipaseC), which has both phospholipase C (PLC) and sphingomyelinase (SMase) activities [3,4], and θ-toxin (or perfringlysin O), which is a pore-forming and cholesterol-dependent cytolysin [5,6]. The infection progresses so rapidly that death precedes diagnosis in some patients and, the development of an effective therapy for treating patients with C. perfringens-mediated myonecrosis is of utmost importance. The well-known virulence factors produced by C. perfringens type A are α-toxin Using a mouse model of C. perfringens-mediated myonecrosis, it was reported that α-toxin-deficient and θ-toxin-deficient strains delay the spread of muscle necrosis [7]. Α-Toxin and θ-toxin enhance intravascular cell aggregation, leading to vascular occlusion, and impair the host immune response by impeding inflammatory cell infiltration to the site of the infection, which is a hallmark of clostridial myonecrosis [11,12,13,14,15]. C. perfringens produces other toxins and enzymes, including a collagenase, hyaluronicdase, sialidases, and the cysteine protease α-clostripain [5,18]

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