Clostridium difficile toxins

Important members of this toxin family are Clostridium difficile toxins A and B, which are implicated in antibiotics-associated diarrhea and pseudomembranous colitis. The large clostridial cytotoxins are single-chain toxins with molecular masses of 250-308 kDa. The enzyme domain is located at the N terminus. The toxins are taken up from an acidic endosomal compartment. They glucosylate RhoA at Thr37 also, Rac and Cdc42 are substrates. Other members of this toxin family such as Clostridium sordellii lethal toxin possess a different substrate specificity and modify Rac but not Rho. In addition, Ras subfamily proteins (e.g., Ras, Ral, and Rap) are modified. As for C3, they are widely used as tools to study Rho functions [2] [4]. 

Hecht G, C Pothoulakis, JT LaMont, JL Madara. (1988). Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J Clin Invest 82 1516-1524. 

Lima AA, Innes DJ Jr, Chadee K, Lyerly DM, Wilkins TD, Guerrant RL Clostridium difficile toxin A. Interactions with mucus and early sequential histopathologic effects in rabbit small intestine. Lab Invest 1989 61 419 125. 

Eichel-Streiber C, Warfolomeow I, Knautz D, Sauerborn M, Hadding U Morphological changes in adherent cells induced by Clostridium difficile toxins. Biochem Soc Trans 1991 19 1154-1160. 

Just I, Selzer J, Wilm M, von Eichel-Streiber C, Mann M, Aktories K Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 1995 375 500-503. 

Brito GA, Sullivan GW, Ciesla WP Jr, Carper HT, Mandell GL, Guerrant RL Clostridium difficile toxin A alters in vitro-adherent neutrophil morphology and function. J Infect Dis 2002 185 1297-1306. 

Flegel WA, Muller F, Daubener W, Fischer HG, Hadding U, Northoff H Cytokine response by human monocytes to Clostridium difficile toxin A and toxin B. Infect Immun 1991 59 3659-3666. 

Jefferson KK, Smith MF Jr, Bobak DA Roles of intracellular calcium and NF-kappa B in the Clostridium difficile toxin A-induced up-regulation and secretion of IL-8 from human monocytes. JImmunol 1999 163 5183-5191. 

Alcantara C, Stenson WF, Steiner TS, Guerrant RL Role of inducible cyclooxygenase and prostaglandins in Clostridium difficile toxin A-induced secretion and inflammation in an animal model. J Infect Dis 2001 184 648-652. 

Pothoulakis C, Sullivan R, Malnick DA, Triad-afilopoulos G, Gadenne AS, Meshulam T, La-Mont JT Clostridium difficile toxin A stimulates intracellular calcium release and chemo-tactic response in human granulocytes. J Clin Invest 1988 81 1741-1745. 

Wershil BK, Castagliuolo I, Pothoulakis C Direct evidence of mast cell involvement in Clostridium difficile toxin A-induced enteritis in mice. Gastroenterology 1998 114 956-964. 

Castagliuolo I, Keates AC, Qiu B, Kelly CP, Nikulasson S, Leeman SE, Pothoulakis C Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats. Proc Natl Acad SciUSA 1997 94 4788-4793. 

A 75- year-old woman is hospitalized for pneumonia and treated with an intravenous antibiotic. On day threet she develops severe diarrhea. Stool is positive for Clostridium difficile toxin What is the best treatment ... 

Ho, J. G., Greco, A., Rupnik, M., and Ng, K. K. (2005). Crystal structure of receptorbinding C-terminal repeats from Clostridium difficile toxin A. Proc. Natl. Acad. Sci. USA 102, 18373-18378. 

Dallas, S. D., and Rolfe, R. D. (1998). Binding of Clostridium difficile toxin A to human milk secretory component. /. Med. Microbiol. 47, 879-888. 

Shen A, Lupardus PJ, Gersch MM, Puri AW, Albrow VE, Garcia KC, Bogyo M (2011) Defining an allosteric circuit in the cysteine protease domain of Clostridium difficile toxins. Nat Struct Mol Biol 18 364... 

I. Florin and M. Thelestam (1984). Polyphosphate-mediated protection from cellular intoxication with Clostridium difficile toxin B. Biochim. Biophys. Acta, 805, 131-136. 

Reinert DJ, Tank T, Aktories K, Schulz GE. Structural basis for the function of Clostridium difficile toxin B.J. Mol. Biol. 2005 351 973-981. 

In acute exacerbations of inflammatory bowel disease a gastrointestinal infection should always be excluded by stool microscopy and culture, and testing for Clostridium difficile toxin. Measures to correct anaemia, fluid and electrolyte abnormalities and to improve the general nutritional state are also important. Antidiarrhoeals should be used with extreme caution in active colitis and are contraindicated if the disease is severe. They can lead to toxic dilatation of the colon, with perforation. 

Talbot RW, Walker RC, Beart RW Jr. Changing epidemiology, diagnosis, and treatment of Clostridium difficile toxin-associated colitis. Br J Surg 1986 73(6) 457-60. 

Mardh PA, Helin I, Colleen I, Oberg M, Holst E. Clostridium difficile toxin in faecal specimens of healthy children and children with diarrhoea. Acta Paediatr Scand 1982 71(2) 275-8. 

Brown E, Talbot GH, Axehod P, Provencher M, Hoegg C. Risk factors for Clostridium difficile toxin-associated diarrhea. Infect Control Hosp Epidemiol 1990 ll(6) 283-90. 

A 63-year-old hjrpertensive woman, who had a carcinoma of the distal esophagus resected 19 months earlier, developed chronic diarrhea. Clostridium difficile toxin was identified in her stools and the diarrhea resolved after treatment with metronidazole. Enalapril was added to her antihypertensive treatment, and 3 months later the diarrhea recurred. Stool examination was negative and there was no Clostridium difficile toxin. Her condition worsened and she lost 5 kg in weight She had marked eosinophiha (2.4 x 10 /1), and a small bowel biopsy showed mild chronic inflammation and edema, partial villous atrophy, and large clusters of eosinophils in the lamina propria with some focal infiltration of the epithelium. She stopped taking enalapril and her diarrhea promptly abated and the eosinophil count fell to 0.5 X 10 /1 at 3 weeks and 0.1 x 10 /1 at 2 months. 

Meadoweroft AM, Diaz PR, Latham GS. Clostridium difficile toxin-induced colitis after use of clindamycin phosphate vaginal cream. Ann Pharmacother 1998 32(3) 309-11. 

A 29-year-old man was given mycophenolate and tacrolimus for an episode of renal transplant rejection that occurred 6.5 years after transplantation. Four weeks after tacrolimus was begun, he had diarrhea, nausea, and malaise. There was C. difficile toxin in the stools, and his symptoms abated with metronidazole. About 1 month later, he developed diarrhea, fever, and severe dehydration. Clostridium difficile toxin was again detected in the stools, and his symptoms completely resolved with oral vancomycin and withdrawal of tacrolimus. 

Prepens U, Just I, Von Eichel-Streiber C et al. (1996) Inhibition of FcsRI-mediated activation of rat basophilic leukemia cells by Clostridium difficile toxin B (mono-glucosyltransferase). In J. Biol. Chem. 271 7324-9 Reuner KH, Presek P, Boschek CB et al. (1987) Botulinum C2 toxin ADP-ribosylates actin and disorganizes the microfilament network in intact cells. In Eur. J. Cell Biol. 43 134-40... 

Fig. 1. Schematic model depicting the domain structure of the Clostridium difficile toxins. See text for further discussion...

Arnon SS, Mills DC, Day PA, el al. (1984) Rapid death of infant rhesus monkeys injected with Clostridium difficile toxins A and B Physiologic and pathologic basis. In J. Pediatr. 104 34-40. 

Barroso LA, Wang SZ, Phelps CJ, et al. (1990) Nucleotide sequence of the Clostridium difficile toxin B gene. In Nucl. Acids Res. 18 4004. 

Barroso LA, Moncrief JS, Lyerly DM, et al. (1994) Mutagenesis of the Clostridium difficile toxin B gene and effect on cytotoxic activity. In Microb. Pathogen. 16 297-303. 

Caspar M, Florin I, Thelestam M (1987) Calcium and calmodulin in cellular intoxication with Clostridium difficile toxin B. In J. Cell. Physiol. 132 168—172. 

Castagliuolo I, LaMont JT, Letourneau R, etal. (1994) Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. In Gastroenterol. 107 657—665. 

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