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Infection and Immunity, September 2004, p. 5204-5215, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5204-5215.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Effects of Clostridium perfringens Alpha-Toxin (PLC) and Perfringolysin O (PFO) on Cytotoxicity to Macrophages, on Escape from the Phagosomes of Macrophages, and on Persistence of C. perfringens in Host Tissues

David K. O'Brien and Stephen B. Melville*

Department of Biology, Virginia Tech, Blacksburg, Virginia

Received 16 February 2004/ Returned for modification 3 May 2004/ Accepted 20 May 2004

Clostridium perfringens is the most common cause of clostridial myonecrosis (gas gangrene). Polymorphonuclear cells (PMNs) appear to play only a minor role in preventing the onset of myonecrosis in a mouse animal model of the disease (unpublished results). However, the importance of macrophages in the host defense against C. perfringens infections is still unknown. Two membrane-active toxins produced by the anaerobic C. perfringens, alpha-toxin (PLC) and perfringolysin O (PFO), are thought to be important in the pathogenesis of gas gangrene and the lack of phagocytic cells at the site of infection. Therefore, C. perfringens mutants lacking PFO and PLC were examined for their relative cytotoxic effects on macrophages, their ability to escape the phagosome of macrophages, and their persistence in mouse tissues. C. perfringens survival in the presence of mouse peritoneal macrophages was dependent on both PFO and PLC. PFO was shown to be the primary mediator of C. perfringens-dependent cytotoxicity to macrophages. Escape of C. perfringens cells from phagosomes of macrophage-like J774-33 cells and mouse peritoneal macrophages was mediated by either PFO or PLC, although PFO seemed to play a more important role in escape from the phagosome in peritoneal macrophages. At lethal doses (109) of bacteria only PLC was necessary for the onset of myonecrosis, while at sublethal doses (106) both PFO and PLC were necessary for survival of C. perfringens in mouse muscle tissue. These results suggest PFO-mediated cytotoxicity toward macrophages and the ability to escape macrophage phagosomes may be important factors in the ability of C. perfringens to survive in host tissues when bacterial numbers are low relative to those of phagocytic cells, e.g., early in an infection.

* Corresponding author. Mailing address: Department of Biology, Virginia Tech, 2119 Derring Hall, Blacksburg, VA 24061-0406. Phone: (54) 231-1441. Fax: (540) 231-9307. E-mail: melville{at}vt.edu.

Editor: V. J. DiRita

Infection and Immunity, September 2004, p. 5204-5215, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5204-5215.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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