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Infection and Immunity, September 2001, p. 5487-5493, Vol. 69, No. 9
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.9.5487-5493.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

pH-Enhanced Cytopathic Effects of Clostridium sordellii Lethal Toxin

Maen Qa'Dan, Lea M. Spyres, and Jimmy D. Ballard*

Department of Botany and Microbiology, The University of Oklahoma, Norman, Oklahoma 73019

Received 11 April 2001/Returned for modification 30 May 2001/Accepted 15 June 2001

Clostridium sordellii lethal toxin (TcsL) is a large clostridial toxin (LCT) that glucosylates Ras, Rac, and Ral. TcsL differs from other LCTs because it modifies Ras, which does not cycle from cytosol to membrane. By using a suite of inhibitors, steps in cell entry by TcsL were dissected, and entry appears to be dependent on endosomal acidification. However, in contrast to TcdB, TcsL was substantially slower in its time course of entry. TcsL cytopathic effects (CPE) were blocked by bafilomycin A1 and neutralized by antiserum up to 2 h following treatment of cells with the toxin. The slow time course of intoxication and relatively high cytopathic dose were alleviated by exposing TcsL to acid pH, resulting in a time course similar to that of TcdB. The optimal pH range for activation was 4.0 to 5.0, which increased the rate of intoxication over 5-fold, lowered the minimal intoxicating dose by over 100-fold, and allowed complete substrate modification within 2 h, as shown by differential glucosylation. Fluorescence analysis of TcsL with 2-(p-toluidinyl) naphthalene-6-sulfonic acid as a probe suggested the acid pH stimulated a hydrophobic transition in the protein, a likely prelude to membrane insertion. Finally, acid entry by TcsL caused TcdB-like morphological changes in CHO cells, which suggestings that acid activation may impact substrate recognition profiles for TcsL.

* Corresponding author. Mailing address: The University of Oklahoma, 770 Van Vleet Oval, Norman, OK 73019. Phone: (405) 325-5133. Fax: (405) 325-7619. E-mail: Jballard{at}ou.edu.

Infection and Immunity, September 2001, p. 5487-5493, Vol. 69, No. 9
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.9.5487-5493.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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