| More

Update on the toxins of Clostridium perfringens and their actions

Views: 146 Downloads: 71


Clostridia appeared as a distinct class, approximately 2.7 billion years ago, before the initial formation of oxygen. Clostridium perfringens is widely distributed throughout the environment due to its ability to form spores. Furthermore, it is a member of intestinal microbiota in animals and human. In 2002, the complete genome of C perfringens strain 13 was published. Genomic analysis has revealed that C. perfringens lacks the genetic machinery to produce 13 essential amino acids and it obtains these in vivo via the action of its toxins. Toxins of C perfringens can be divided into major, minor and enterotoxin. C perfringens strains are classified into five toxinotypes (A, B, C, D and E), based on the production of four major toxins. Alpha toxin is the best and most studied major toxin of C perfringens and it was the first bacterial toxin established to possess enzymatic activity. It has haemolytic, necrotic and cytolytic activity, it can lyse platelets and leukocytes and it can damage fibroblasts and muscle cell membranes. Expression of epa gene, which is responsible for the production of alpha toxin by C perfringens, is down-regulated in the normal healthy gut, but it is upregulated to initiate enteric disease in response to an environmental signal. C perfringens appears to be regulated in a quorum sensing manner, using oligopeptides, AI-2 or both, to regulate expression of the epa gene, and thus the synthesis of alpha toxin. Beta toxin is recognized as an important agent in necrotic enteritis of humans and it is the second most lethal C. perfringens toxin following epsilon toxin. Beta toxin is a membrane spanning protein that oligomerizes to form channels in susceptible cells or it primarily acts as a neurotoxin. Epsilon toxin is the most potent of the C. perfringens toxins and the third most potent neurotoxin from the Clostridium spp., following botulinum and tetanus toxins. Epsilon toxin of C perfringens type D causes enterotoxaemia and pulpy kidneys disease of lambs. Iota toxin causes disruption of the actin cytoskeleton and cell barrier integrity and it is the less toxic of the major toxins of C perfringens. Although C perfringens enterotoxin is not classified as one of the major toxins of C perfringens, it is the third most common cause of food poisoning in industrialized nations. It is not secreted by the cells of growing bacteria, but it is released only with the sporulation of C perfringens. Not all strains of C perfringens carry the epe gene, which is responsible for the production of enterotoxin. Theta toxin is a pore-forming cytolysin that can lyse red blood cells. It is produced by all types of C perfringens. Together with alpha-toxin, theta-toxin modulates the host inflammatory response. ß2 toxin is a pore forming toxin which is involved in necrotic enteritis of swine and horse, in haemorragic enteritis of bovine in diarrhea cases of dogs and along with enterotoxin in diarrhea cases of humans. Recently, -NetB, a novel toxin that is associated with broiler necrotic enteritis, has been described. The mechanism of its action seems to involve the formation of small hydrophilic pores. Other toxins of C. perfringens include λ-toxin, ô-toxin, μ-toxin, v-toxin, κ-toxin, a-clostripain like protease and neuraminidase/sialidase. These toxins can act as enzymes, while many of them can act synergically or supplementally with major pore forming toxins. Potentially, C. perfringens might produce more toxins, which have not been identified. Finally, the actions of C. perfringens toxins, major or minor, in some diseases have not been figured out.


Clostridium perfringens; toxins

Full Text:



Awad MM, Ellemor DM, Boyd RL, Emmins JJ, Rood JI (2001) Synergistic effects of alpha-toxin and perfringolysin Ο in Clostridium perfringens-mediated gas gangrene. Infection and Immunity, 69:7904-7910.

Biberstein E (1990) The Clostridia. Review of Veterinary Microbiology. Blackwell Scientific Publications, Ine, London, UK, pp 295-310.

Brock T, Madigan M, Martinko J, Parker J (1994) Biology of microorganisms. 7th Edition, Prentice-Hall Ine, New Jersey, USA. Brooks M, Sterne M, Warrack G (1957) A reassessment of the criteria used for type differentiation of Clostridium perfringens. Journal of Pathology and Bacteriology, 74:185-195.

Brown CC, Baker DC and Barker IK (2007) Infectious and parasitic diseases of the alimentary tract. In: Jubb, Kennedy and Palmer's pathology of domestic animals. 5th Edition. Elsevier Health

Sciences, pp 135-279.

Bryant AE, Chen RY, Nagata Y, Wang Y, Lee CH, Finegold S, Guth PH, Stevens DL (2000) Clostridial gas gangrene. II. Phospholipase C-induced activation of platelet gpllbllla mediates vascular occlusion and myonecrosis in Clostridium perfringens gas gangrene. Journal of Infection Diseases, 182:808-815.

Bryant AE, Stevens DL (1996) Phospholipase C and perfringolysin Ο from Clostridium perfringens up-regulate endothelial cellleukocyte adherence molecule 1 and intercellular leukocyte

adherence molecule 1 expression and induce interleukin-8 synthesis in cultured human umbilical vein endothelial cells. Infection and Immunity, 64:358-62.

Bunting Μ, Lorant DE, Bryant ΑΕ, Zimmerman GA, Mclntyre TM, Stevens DL, Prescott SM (1997) Alpha toxin from Clostridium perfringens induces proinflammatory changes in endothelial cells. Journal of Clinical Investigation, 100:565-574.

Cato E, George W, Finegold S (1986) Genus Clostridium. In: Bergey s Manual of Systematic Bacteriology. Baltimore, USA, pp 1179-1182.

Collie RE, McClane Β A (1998) Evidence that the enterotoxin gene can be episomal in Clostridium perfringens isolates associated with non-food-borne human gastrointestinal diseases. Journal of Clinical Microbiology, 36:30-36.

Collins M, Lawson P, Willems A, Cordoba J, Fernandez-Garayzabal J, Garcia P, Cai J, Hippe Η, Farrow J (1994) The phylogeny of the genus Clostridium: proposal of five new genera and eleven new species combinations. International Journal of Systematic Bacteriology, 44:812-826!

Cooper K, Songer G (2009) Necrotic enteritis in chickens: A paradigm of enteric infection by Clostridium perfringens type A. Anaerobe, 15:55-60.

Fisher D, Miyamoto K, Harrison B, Akimoto S, Sarker M, McClane Β (2005) Association of beta2 toxin production with Clostridium perfringens type A human gastrointestinal disease isolates carrying a plasmid enterotoxin gene. Molecular Microbiology, 56:747-762.

Flores-D az M, Thelestam M, Clark G, Titball R, Alape-Gir η A (2004) Effects of Clostridium perfringens phospholipase C in mammalian cells. Anaerobe, 10:115-123.

Frey J, Vileie M (2003) Molecular genetics of Clostridium perfringens toxins. In: European Concerted Action QLK2-CT2001-01267.

Protein toxins of the genus Clostridium and vaccination. Liege, Belgium, pp 45-51.

Fujita K, Katahira J, Horiguchi Y, Sonoda N, Furuse M and Tsukita S (2000) Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3, a tight junction integral membrane protein. FEBS Letters, 476. pp 258-261.

Gatsos X (2007) The development of live vectored vaccines targeting the alpha-toxin of Clostridium perfringens for the prevention of necrotic enteritis in poultry. PhD thesis. Biotechnology and Environmental Biology School of Applied Science, RMIT University, Melbourne, Victoria, Australia.

Gibert M, Jolivet-Reynaud C, Popoff MR, Jolivet-Renaud C (1997) Beta2 toxin, a novel toxin produced by Clostridium perfringens. Gene, 203:65-73.

Gibert M, Petit L, Raffestin S, Okabe A, Popoff MR (2000) Clostridium perfringens iota-toxin requires activation of both binding and enzymatic components for cytopathic activity. Infection and Immunity, 68:3848-3853.

Gilbert R, Jimenez J, Chen S, Andrew P, Saibil H (2000) Structural basis of pore formation by cholesterol-binding toxins. International Journal of Medicine Microbiology, 290:389-394.

Hatheway C (1990) Toxigenic Clostridia. Clinical Microbiology Revision. 3:66-98.

Herholz C, Miserez R, Nicolet J, Frey J, Popoff M, Gibert M, Gerber H, Straub R (1999) Prevalence of beta2-toxigenic Clostridium perfringens in horses with intestinal disorders. Journal of Clinical Microbiology, 37:358-61.

Hirsh DC and Biberstein EL (2004) Clostridium. In: Veterinary Microbiology. 2nd Edition. Blackwell Publishing, pp 198-214.

Immerseel F, De Buck J, Pasmans F, Huyghebaert G, Haesebrouck F and Ducatelle R.(2004) Clostridium perfringens in poultry: An emerging threat for animal and public health. Avian Pathology, 33:537-549.

Immerseel F, Rood J, Moore R, Titball R (2009) Rethinking our understanding of the pathogenesis of necrotic enteritis in chickens. Trends in Microbiology, 17:32-36.

Johansson A (2006) Clostridium perfringens: the causal agent of necrotic enteritis in poultry. PhD thesis, Swedish University of Agricultural Sciences, Uppsala, Sweden.

Johnson C (1989) Clostridium perfringens food poisoning. In: Anaerobic infections in humans. Academic Press. London, UK, pp 629-638.

Jost B, Billington HSJ, Trinh HT, Bueschel DM, Songer JG (2005) Atypical cpb2 genes, encoding beta2-toxin in Clostridium perfringens isolates of nonporcine origin. Infection and Immunity,


Keyburn A, Sheedy S, Ford M, Williamson M, Awad M, Rood J, Moore R (2006) Alpha-toxin of Clostridium perfringens is not an essential virulence factor in necrotic enteritis in chickens. Infection and Immunity, 74:6496-6500.

Krieg Ν (1984) Bergey's manual of systematic bacteriology, vol. 1. Williams and Wilkins, Baltimore, USA.

Lahti P, Heikinheimo A, Johansson T, Korkeala Η (2008) Clostridium perfringens type A strains carrying a plasmid-borne enterotoxin gene (genotype IS1151-cpe or IS1470-like-cpe) as a common cause of food poisoning. J Clin Microbiol, 46:371-373.

Lebrun M, Filée P, Mousset Β, Desmecht D, Galleni M, Mainil JG and Linden A (2007) The expression of Clostridium perfringens consensus b2 toxin is associated with bovine enterotoxaemia syndrome. Veterinary Microbiology, 120:151-157.

Leslie D, Fairweather N, Pickard D, Dougan G, Kehoe M (1989) Phospholipase C and haemolytic activities of Clostridium perfringens alpha-toxin cloned in Escherichia coli: sequence and homology with a Bacillus cereus phospholipase. C Mol Microbiol,


Lu LG, Hume ME, Pillai SD (2005) Autoinducer 2-like activity in poultry-associated enteric bacteria in response to subtherapeutic antibiotic exposure. Avian Diseases, 49:74-80.

Manich M, Knapp Ο, Gibert M, Maier E, Jolivet-Reynaud C, Geny B, Benz R, Popoff M (2008) Clostridium perfringens delta toxin is sequence related to beta toxin, NetB, and Staphylococcus poreforming toxins, but shows functional differences. PLoS One, 3:e3764.

Mantis NJ (2005) Vaccines against the category Β toxins: Staphylococcal enterotoxin B, epsilon toxin and ricin. Adv Drug Deliv Rev, 57:1424-1439.

McClane BA (2007) Clostridium perfringens. In: Food Microbiology: Fundamentals and Frontiers. 3rd Edition. ASM Press, Washington, USA, pp 423-444.

McClane BA (2001) The complex interactions between Clostridium perfringens enterotoxin and epithelial tight junctions. Toxicon, 39:1781-1791.

McDevitt R, Brooker J, Acamovic T, Sparks Ν (2006) Necrotic enteritis: a continuing challenge for the poultry industry. World's Poultry Science Journal, 62:221-247.

Minami J, Katayama S, Matsushita O, Matsushita C, Okabe A (1997) Lambda-toxin of Clostridium perfringens activates the precursor of epsilon-toxin by releasing its N- and C-terminal peptides. Microbiol Immunol, 41:527-535.

Miwa N, Nishina T, Kubo S and Honda H (1997) Most probable numbers of enterotoxigenic Clostridium perfringens in intestinal contents of domestic livestock detected by nested PCR. Journal of Veterinary Medical Science, 59:557-560.

Miwa N, Nishina T, Kubo S, Atsumi M and Honda H (1998) Amount of enterotoxigenic Clostridium perfringens in meat detected by nested PCR. International Journal of Food Microbiolog, 42:195-200.

Miyata S, Minami J, Tamai E, Matsushita O, Shimamoto S, Okabe A (2002) Clostridium perfringens epsilon-toxin forms a heptameric pore within the detergent-insoluble microdomains of Madin-Darby canine kidney cells and rat synaptosomes. J Biol Chem, 277:39463-39468.

Nagahama M, Hayashi S, Morimitsu S, Sakurai J (2003) Biological activities and pore formation of Clostridium perfringens beta toxin in HL 60 cells. J Biol Chem, 278:36934-36941.

Nagahama M, Michiue K, Mukai M, Ochi S, Sakurai J (1998). Mechanism of membrane damage by Clostridium perfringens alpha-toxin. Microbiol Immunol, 42:533-8.

Naylor CE, Jepson M, Crane DT, Titball RW, Miller J, Basak AK, Bolgiano Β (1999) Characterisation of the calcium-binding Cterminal domain of Clostridium perfringens alpha-toxin. J Mol Biol, 294:757-770.

Ninomiya M, Matsushita O, Minami J, Sakamoto H, Nakano M,Okabe A (1994) Role of alpha-toxin in Clostridium perfringens infection determined by using recombinants of C. perfringens and

Bacillus subtilis. Infection and Immunity, 62:5032-5039.

Novak JS, Fratamico PM (2004) Evaluation of ascorbic acid as a quorum-sensing analogue to control growth, sporulation, and enterotoxin production in Clostridium perfringens. Journal of

Food Science, 69:FMS72-FMS78.

Perelle S, Gibert M, Boquet Ρ, Popoff MR (1993) Characterization of Clostridium perfringens iota-toxin genes and expression in Escherichia coli. Infection and Immunity, 61:5147-5156.

Petit L, Gibert M, Popoff M (1999) Clostridium perfringens: Toxinotype and genotype. Trends in Microbiology, 7:104-110.

Petit L, Maier E, Gibert M, Popoff M, Benz R (2001) Clostridium perfringens epsilon toxin induces a rapid change of cell membrane permeability to ions and forms channels in artificial lipid bilayers. J Biol Chem, 276:15736-15740.

Phillips-Jones MK (2000) Use of a lux reporter system for monitoring rapid changes in alpha -toxin gene expression in Clostridium perfringens during growth. FEMS Microbiology-Letter, 188:29-33.

Quinn P, Carter M, Markey B, Carter G (1994) Clinical Veterinary Microbiology. Wolfe Publishing. London, UK.

Robertson SL, Smedley JG 3rd, Singh U, Chakrabarti G, Van Itallie CM, Anderson JM and McClane BA (2007) Compositional and stoichiometric analysis of Clostridium perfringens enterotoxin complexes in Caco-2 cells and claudin 4 fibroblast transfectants. Cellular Microbiology, 9: 2734-2755.

Rood J, Cole S (1991) Molecular genetics and pathogenesis of Clostridium perfringens. Microbiological Reviews, 55:621-648.

Sakurai J, Fujii Y, Dezaki K, Endo Κ (1984) Effect of Clostridium perfringens beta toxin on blood pressure of rats. Microbiol Immunol, 28:23-31.

Sakurai J, Fujii Y, Matsuura M, Endo Κ (1981) Pharmacological effect of beta toxin of Clostridium perfringens type C on rats. Microbiol Immunol, 25:423-432.

Sakurai J, Nagahama M, Ochi S (1997) Major toxins of Clostridium perfringens. Toxin Reviews, 16:195-214.

Sakurai, J, Duncan CL (1978) Some properties of beta-toxin produced by Clostridium perfringens type C. Infection and Immunity, 21:678-680.

Shatursky O, Bayles R, Rogers M, Jost BH, Songer JG, Tweten RK (2000) Clostridium perfringens beta-toxin forms potentialdependent, cation-selective channels in lipid bilayers. Infection and Immunity, 68:5546-5551.

Shimizu T, Ohtani K, Hirakawa H, Ohshima K, Yamashita A, Shiba T, Ogasawara N, Hattori M, Kuhara S, Hayashi H (2002) Complete genome sequence of Clostridium perfringens, an anaerobic flesh-eater. In: Proceedings of the National Academy of Sciences of the United States of America, 99:996-1001.

Smedley JG 3rd, Fisher DJ, Sayeed S, Chakrabarti G and McClane BA (2004) The enteric toxins of Clostridium perfringens. Reviews of Physiology, Biochemistry and Pharmacology, 152:183-204.

Songer J (1996) Clostridial enteric diseases of domestic animals. Clinical Microbiology Reviews, 9:216-234.

Steinthorsdottir V, Halldorsson H, Andresson OS (2000) Clostridium perfringens beta-toxin forms multimeric transmembrane pores in human endothelial cells. Microb Pathog, 28:45-50.

Stevens DL, Bryant AE (1997) Pathogenesis of Clostridium perfringens infection: mechanisms and mediators of shock. Clin Infect Dis, 2 (Suppl):S160-164.

Tamai E, Ishida T, Miyata S, Matsushita O, Suda H, Kobayashi S, Sonobe H, Okabe A (2003) Accumulation of Clostridium perfringens epsilon toxin in the mouse kidney and its possible biological significance. Infection and Immunity, 71: 5371-5375.

Titball R, Naylor C, Basak A (1999) The Clostridium perfringens –a toxin. Anaerobe, 5:51-64.

Titball RW (1997) Clostridial phospholipases. In: The Clostridia: Molecular biology and pathogenesis. Academic Press, San Diego, pp 223-242.

Titball RW, Fearn AM, Williamson ED (1993) Biochemical and immunological properties of the C-terminal domain of the alphatoxin of Clostridium perfringens. FEMS Microbiol Lett, 110:45-50.

Titball RW, Hunter SE, Martin KL, Morris BC, Shuttleworth AD, Rubidge T, Anderson DW, Kelly DC (1989) Molecular cloning and nucleotide sequence of the alpha-toxin (phospholipase C) of Clostridium perfringens. Infection and Immunity, 57:367-376.

Tsutsui K, Minami J, Matsushita O, Katayama S, Taniguchi Y, Nakamura S, Nishioka M, Okabe A (1995) Phylogenetic analysis of phospholipase C genes from Clostridium perfringens types A to

E and Clostridium novyi. Journal of Bacteriology, 177:7164-7170.

Varga J, Nguyen V, O'Brien D, Rodgers K, Walker R, Melville S (2006) Type IV pili-dependent gliding motility in the Grampositive pathogen Clostridium perfringens and other Clostridia.

Molecular Microbiology, 62:680-694.

Wages D, Opengart Κ (2003) Necrotic enteritis. In: Diseases of Poultry. 11th ed, Iowa State Press. Blackwell Publishing Company. Iowa, USA, pp 781-785.

Worthington RW, Mulders MS (1975) Effect of Clostridium perfringens epsilon toxin on the blood brain barrier of mice. Onderstepoort J Vet Res, 42:25-27.

Xavier KB, Bassler BL (2003) LuxS quorum sensing: more than just a numbers game. Current Opinion in Microbiology, 6:191-197.


  • There are currently no refbacks.