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Infection and Immunity, August 2002, p. 4353-4361, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4353-4361.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Clostridium septicum Alpha-Toxin Is Active against the Parasitic Protozoan Toxoplasma gondii and Targets Members of the SAG Family of Glycosylphosphatidylinositol-Anchored Surface Proteins

Michael J. Wichroski,1 Jody A. Melton,2 Carolyn G. Donahue,1 Rodney K. Tweten,2 and Gary E. Ward1*

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont 05405,1 Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 731902

Received 22 January 2002/ Returned for modification 5 March 2002/ Accepted 8 May 2002

As is the case with many other protozoan parasites, glycosylphosphatidylinositol (GPI)-anchored proteins dominate the surface of Toxoplasma gondii tachyzoites. The mechanisms by which T. gondii GPI-anchored proteins are synthesized and transported through the unusual triple-membrane structure of the parasite pellicle to the plasma membrane remain largely unknown. As a first step in developing tools to study these processes, we show here that Clostridium septicum alpha-toxin, a pore-forming toxin that targets GPI-anchored protein receptors on the surface of mammalian cells, is active against T. gondii tachyzoites (50% effective concentration, 0.2 nM). Ultrastructural studies reveal that a tight physical connection between the plasma membrane and the underlying membranes of the inner membrane complex is locally disrupted by toxin treatment, resulting in a massive outward extension of the plasma membrane and ultimately lysis of the parasite. Toxin treatment also causes swelling of the parasite endoplasmic reticulum, providing the first direct evidence that alpha-toxin is a vacuolating toxin. Alpha-toxin binds to several parasite GPI-anchored proteins, including surface antigen 3 (SAG3) and SAG1. Interestingly, differences in the toxin-binding profiles between the virulent RH and avirulent P strain were observed. Alpha-toxin may prove to be a powerful experimental tool for molecular genetic analysis of GPI anchor biosynthesis and GPI-anchored protein trafficking in T. gondii and other susceptible protozoa.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405. Phone: (802) 656-4868. Fax: (802) 656-8749. E-mail: gward{at}zoo.uvm.edu.

Editor: J. T. Barbieri

Infection and Immunity, August 2002, p. 4353-4361, Vol. 70, No. 8
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.8.4353-4361.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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