CLOSTRIDIUM-PERFRINGENS INVASIVENESS IS ENHANCED BY EFFECTS OF THETA-TOXIN UPON PMNL STRUCTURE AND FUNCTION - THE ROLES OF LEUKOCYTOTOXICITY AND EXPRESSION OF CD11 CD18 ADHERENCE GLYCOPROTEIN/

Clostridium perfringens infections are characterized by the lack of an inflammatory response at the site of infection and rapidly progressiv e margins of tissue necrosis. Studies presented here investigated the role of theta toxin from C. perfringens in the pathophysiology of thes e events. Mice passively immunized with neutralizing monoclonal antibo dy against theta toxin and challenged with an LD(100) of log phase C. perfringens had significantly less mortality than untreated controls. Intramuscular injection of killed, washed C. perfringens in mice induc ed a massive time-dependent influx of polymorphonuclear leukocytes (PM NL) into tissue; injection of either viable, washed C. perfringens or killed organisms plus theta toxin dramatically attenuated PMNL influx although PMNL accumulated in adjacent vessels. The anti-inflammatory e ffects could not be attributed to an absence of chemoattractants since C. perfringens proteins had chemotactic factor activity, and killed b acilli generated serum-derived chemotactic factors. Scanning and trans mission electron microscopy demonstrated the dramatic leukocidal effec ts of high doses of theta toxin on PMNL. In contrast, sublethal concen trations of theta toxin primed PMNL chemiluminescence, disrupted PMNL cytoskeletal actin polymerization/disassembly, and stimulated function al upregulation of CD11b/CD18 adherence glycoprotein. In summary, thes e results demonstrate that theta toxin is an important virulence facto r in C. perfringens infection. In a concentration-dependent fashion, t heta toxin contributes to the pathogenesis of clostridial gangrene by direct destruction of host inflammatory cells and tissues, and by prom oting dysregulated PMNL/endothelial cell adhesive interactions.