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Infection and Immunity, June 2004, p. 3120-3128, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3120-3128.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Degeneration and Regeneration of Murine Skeletal Neuromuscular Junctions after Intramuscular Injection with a Sublethal Dose of Clostridium sordellii Lethal Toxin

Julien Barbier,1 Michel R. Popoff,2 and Jordi Molgó1*

Laboratoire de Neurobiologie Cellulaire et Moléculaire, U. P. R. 9040, Centre National de la Recherche Scientifique, Gif-sur-Yvette,1 Centre National de Référence Anaérobies, Institut Pasteur, Paris, France2

Received 10 September 2003/ Returned for modification 14 October 2003/ Accepted 31 January 2004

Clostridium sordellii lethal toxin (LT), a 250-kDa protein which is the bacteria's major virulence factor, belongs to a family of large clostridial cytotoxins which glucosylate small GTP-binding proteins. Here, we report the results of our ex vivo analysis of the structure and function of skeletal neuromuscular tissue obtained from mice at various times after intramuscular injection of a sublethal dose of LT (0.25 ng/g of body wt). The toxin caused, within 24 h, pronounced localized edema, inflammation, myofibril disassembly, and degeneration of skeletal muscle fibers in the injected area, and it glucosylated the muscle tissue's small GTPases. Regeneration of the damaged fibers was evident 6 to 9 days postinjury and was completed by 60 days. The expression of dystrophin, laminin, and fast and neonatal myosin in regenerating fibers, detected by immunofluorescence microscopy, confirmed that LT does not impair the high regenerative capacity of murine skeletal muscle fibers. Functional studies revealed that LT affects muscle contractility and neuromuscular transmission. However, partial recovery of nerve-evoked muscle twitches and tetanic contractions was observed by day 15 postinjection, and extensive remodeling of the neuromuscular junction's nerve terminals and clusters of muscle acetylcholine receptors was still evident 30 days postinjection. In conclusion, to the best of our knowledge, this is the first report to characterize the degeneration and regeneration of skeletal neuromuscular tissue after in vivo exposure to a large clostridial cytotoxin. In addition, our data may provide an explanation for the severe neuromuscular alterations accompanying wound infections caused by C. sordellii.

* Corresponding author. Mailing address: Laboratoire de Neurobiologie Cellulaire et Moléculaire, U. P. R. 9040, C. N. R. S., 1 Avenue de la Terrasse, 91198 Gif-sur-Yvette CEDEX, France. Phone: 33 1 69 82 36 42. Fax: 33 1 69 82 94 66. E-mail: Jordi.Molgo{at}nbcm.cnrs-gif.fr.

Editor: J. T. Barbieri

Infection and Immunity, June 2004, p. 3120-3128, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3120-3128.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Geny, B., Khun, H., Fitting, C., Zarantonelli, L., Mazuet, C., Cayet, N., Szatanik, M., Prevost, M.-C., Cavaillon, J.-M., Huerre, M., Popoff, M. R. (2007). Clostridium sordellii Lethal Toxin Kills Mice by Inducing a Major Increase in Lung Vascular Permeability. Am. J. Pathol. 170: 1003-1017 [Abstract] [Full Text]  


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