Pathologic findings on ruminant enteric clostridial diseases reveal specificities and differences among iota and iota-like toxins

  • Helio S Brito
  • Fernando Camargo Alencar
  • Benedito Albuquerque
  • Marcos G Silva
  • Mellanie KC Felix
  • Daniel S Mulholland
  • Eugênio E Oliveira
  • Luis André M Mariúba
  • Eliane M Sobrinho
  • Igor V Brandi
  • Francisco Carlos F Lobato
  • Alex Sander R Cangussu Federal University of Tocantins
Keywords: iota toxin, iota like toxin, binary toxins, C. perfringens type E, enterotoxemia


The iota toxin (ITX) is a binary enterotoxin produced as a protoxin by Clostridium perfringens (C. perfringens) type E that is activated by proteolytic enzymes in the small intestine of infected animals. By depolymerization of the actin filaments, ITX causes cytoskeleton disorganization of cells promoting the increase of the cell permeability. Here, we conducted this review aiming to advance the understanding of enteric clostridial diseases caused by C. perfringens toxins and the specificity of ITX in the intestinal mucosa lesions. ITX consists of an enzymatic component (Ia) and a binding component (Ib). We screened the recently published histological findings of the ITX effects and its relationship with intestinal enteric diseases. Histologically, hemorrhagic necrosis and multifocal hemorrhage have been observed in the jejunum-ileum mucosa, the small intestine, and the abomasum. Although the diagnosis is still based on the presence of toxins in the intestinal contents and the clinical and/or histological history, it is important to develop novel enterotoxemic indicators capable of establishing precise methods for differentiate the actions of ITX and other toxins involved in the infectious process of C. perfringens type E.


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Alves, G. G.; R. A. M. de Ávila; Chávez-Olórtegui, C. D.; Lobato, F. C. F. (2014). Clostridium perfringens epsilon toxin: The third most potent bacterial toxin known. Anaerobe. 30: 102-107. doi: 10.1016/j.anaerobe.2014.08.016

Assis-Rodrigues, M.; Rodrigues-Sartori, S.; Santos-Totaro, P.; Pinto da Matta, S. (2019). Hystometric evaluation of nickel chronic exposure effects on large instestine of adult Wistar male rats. Revista de Ciencias Agrícolas. 36 (E): 21-30. doi: 10.22267/rcia.1936E.103

Awad, M. M.; Bryant, A. E.; Stevens, D. L.; Rood, J. I. (1995). Virulence studies on chromosomal α‐toxin and Θ‐toxin mutants constructed by allelic exchange provide genetic evidence for the essential role of α‐toxin in Clostridium perfringens‐mediated gas gangrene. Molecular Microbiology. 15: 191-202. doi: 10.1111/j.1365-2958.1995.tb02234.x

Batah, J.; Kobeissy, H.; Pham, P. T. B.; Denève-Larrazet, C.; Kuehne, S.; Collignon, A.; Janoir-Jouveshomme, C.; Marvaud, J. C.; Kansau, I. (2017). Clostridium difficile flagella induce a pro-inflammatory response in intestinal epithelium of mice in cooperation with toxins. Scientific Reports. 7: 1-10. doi: 10.1038/s41598-017-03621-z

Borriello, S. P.; Carman, R. J. (1983). Association of iota-like toxin and Clostridium spiroforme with both spontaneous and antibiotic-associated diarrhea and colitis in rabbits. Journal of Clinical Microbiology. 17 (3): 414-418. doi: 0095-1137/83/030414-05$02.00/0

Brandi, I. V.; Mozzer, O. D.; Vander Jorge, E.; Passos, F. J. V.; Passos, F. M. L.; Cangussu, A. S. R.; Sobrinho, E. M. (2014). Growth conditions of clostridium perfringens type B for production of toxins used to obtain veterinary vaccines. Bioprocess and biosystems engineering. 37 (9): 1737-1742. doi: 10.1007/s00449-014-1146-0

Brandi, I. V.; Santos, E. M. S.; de Carvalho, B. M. A.; Durães, C. A. F.; Farias, P. K. S.; Sari, R. S.; Junior, A. P. (2016). Total combining power: Technique for the evaluation of the quality control process of clostridiosis vaccines. Journal of microbiological methods. 130: 164-168. doi: 10.1016/j.mimet.2016.08.023

Carman, R. J.; Borriello, S. P. (1984). Infectious nature of Clostridium spiroforme-mediated rabbit enterotoxaemia. Veterinary microbiology. 9 (5): 497-502. doi: 10.1016/0378-1135(84)90070-1

Chakravorty, A.; Awad, M. M.; Hiscox, T. J.; Cheung, J. K.; Choo, J. M.; Lyras, D.; Rood, J. I. (2014). Opioid analgesics stop the development of clostridial gas gangrene. Journal of Infectious Diseases. 210: 483-492. doi: 10.1093/infdis/jiu101

Diab, S. S.; Kinde, H.; Moore, J.; Shahriar, M. F.; Odani, J.; Anthenill, L.; Uzal, F. A. (2012). Pathology of Clostridium perfringens type C enterotoxemia in horses. Veterinary Pathology. 49 (2): 255-263. doi: 10.1177/0300985811404710

Domenighini, M.; Rappuoli, R. (1996). Three conserved consensus sequences identify the NAD-binding site of ADP-ribosylating enzymes, expressed by eukaryotes, bacteria and T-even bacteriophages. Molecular Microbiology. 21: 667–674 doi: 10.1046/j.1365-2958.1996.321396.x

Felix, M. K. C.; Deusdará, T. T.; Santos, L. S. S.; Aguiar, R. W. S.; Corrêa, R. F. T.; Brandi, I. V.; Cangussu, A. S. R. (2019). Inactivated alpha toxin from Clostridium novyi type B in nano-emulsion protect partially protects Swiss mice from lethal alpha toxin challenge. Scientific reports. 9 (1): 1-9. doi: 10.1038/s41598-019-50683-2

Ferrarezi, M. C.; Cardoso, T. C.; Dutra, I. S. (2008). Genotyping of Clostridium perfringens isolated from calves with neonatal diarrhea. Anaerobe. 14: 328-331. doi: 10.1016/j.anaerobe.2008.12.001

Filho, E. J. F.; Carvalho, A. U.; Assis, R. A.; Lobato, F. F.; Rachid, M. A.; Carvalho, A. A.; Ferreira, P. M.; Nascimento, R. A.; Fernandes, A. A.; Vidal, J. E.; Uzal, F. A. (2009). Clinicopathologic features of experimental Clostridium perfringens type D enterotoxemia in cattle. Veterinary Pathology. 46: 1213-1220. doi: 10.1354/vp.08-VP-0304-U-FL

Fleming, S. (1985). Enterotoxemia in neonatal calves. Veterinary Clinics of North America: Food Animal Practice. 1 (3): 509-514. doi: 10.1016/S0749-0720(15)31299-8

Freedman, J. C.; Theoret, J. R.; Wisniewski, J. A.; Uzal, F. A.; Rood, J. I.; McClane, B.A. (2015). Clostridium perfringens type A–E toxin plasmids. Research in Microbiology. 166: 264-279. doi: 10.1016/j.resmic.2014.09.004

Fuentes, L.; Lebenkoff, S.; White, K.; Gerdts, C.; Hopkins, K.; Potter, J. E.; Grossman, D.; Project, P. E.; Sciences, R. (2016). Animal models to study the pathogenesis of human Clostridium perfringens infections. Veterinary Microbiology. 93: 292-297. doi: 10.1016/j.vetmic.2015.02.013.Animal

Gibert, M.; Marvaud, J. C.; Pereira, Y.; Hale, M. L.; Stiles, B. G.; Boquet, P.; Lamaze, C.; Popoff, M. R. (2007). Differential requirement for the translocation of clostridial binary toxins: Iota toxin requires a membrane potential gradient. FEBS Letters. 581: 1287-1296. doi: 10.1016/j.febslet.2007.02.041

Gibert, M.; Monier, M. N.; Ruez, R.; Hale, M. L.; Stiles, B. G.; Benmerah, A.; Johannes, L.; Lamaze, C.; Popoff, M. R. (2011). Endocytosis and toxicity of clostridial binary toxins depend on a clathrin-independent pathway regulated by Rho-GDI. Cellular Microbiology. 13: 154-170. doi: 10.1111/j.1462-5822.2010.01527.x

Gibert, M.; Petit, L.; Raffestin, S.; Okabe, A.; Popoff, M. R. (2000). Clostridium perfringens iota-toxin requires activation of both binding and enzymatic components for cytopathic activity. Infection and Immunity. 68: 3848–3853. doi: 10.1128/IAI.68.7.3848-3853.2000

Ghoneim, N. H.; Hamza, D. A. (2017). Epidemiological studies on Clostridium perfringens food poisoning in retail foods. Rev. Sci. Tech. 36 (3): 1025-1032. doi: 10.20506/rst.36.3.2734

Harada, M.; Kondoh, M.; Ebihara, C.; Takahashi, A.; Komiya, E.; Fujii, M.; Mizuguchi, H.; Tsunoda, S. I.; Horiguchi, Y.; Yagi, K.; Watanabe, Y. (2007). Role of tyrosine residues in modulation of claudin-4 by the C-terminal fragment of Clostridium perfringens enterotoxin. Biochemical Pharmacology. 73: 206-214. doi: 10.1016/j.bcp.2006.10.002

Harkness, J. M.; Li, J.; McClane, B. A. (2012). Identification of a lambda toxin-negative Clostridium perfringens strain that processes and activates epsilon prototoxin intracellularly. Anaerobe. 18: 546-552. doi: 10.1016/j.anaerobe.2012.09.001

Ismail, Z. B; Omoush, F. (2019). Abomasal displacement in neonatal dairy calves: Review of recent literature with special emphasis on abomasal torsion. Veterinary World. 12: 1121-1125. doi: 10.14202/vetworld.2019.1121-1125

Jewell, S. A.; Titball, R. W.; Huyet, J.; Naylor, C. E.; Basak, A. K.; Gologan, P.; Winlove, C. P.; Petrov, P. G. (2015). Clostridium perfringens α-toxin interaction with red cells and model membranes. Soft Matter. 11: 7748-7761. doi: 10.1039/c5sm00876j

Keyburn, A. L.; Yan, X. X.; Bannam, T. L.; Van Immerseel, F.; Rood, J. I.; Moore, R. J. (2010). Association between avian necrotic enteritis and Clostridium perfringens strains expressing NetB toxin. Veterinary Research. 41. doi: 10.1051/vetres/2009069

Kim, H.; Byun, J.; Roh, I.; Bae, Y.; Lee, M.; Kim, B.; Songer, J. G.; Jung, B. Y. (2013). First isolation of Clostridium perfringens type E from a goat with diarrhea. Anaerobe. 22: 141-143. doi: 10.1016/j.anaerobe.2013.06.009

Knapp, O.; Benz, M.; Popoff, R. (2016). Pore-forming activity of clostridial binary toxins. Biochimica et Biophysica Acta - Biomembranes. 1858: 512-525. doi: 10.1016/j.bbamem.2015.08.006

Knapp, O.; Maier, E.; Benz, R.; Geny, B.; Popoff, M. R. (2009). Identification of the channel-forming domain of Clostridium perfringens Epsilon-toxin (ETX). Biochimica et Biophysica Acta - Biomembranes. 1788: 2584-2593. doi: 10.1016/j.bbamem.2009.09.020

Li, J.; Adams, V.; Bannam, T. L.; Miyamoto, K.; Garcia, J. P.; Uzal, F. A.; Rood, J. I.; McClane, B. A. (2013). Toxin Plasmids of Clostridium perfringens. Microbiology and Molecular Biology Reviews. 77: 208-233. doi: 10.1128/mmbr.00062-12

Lobato, F. C. F.; Moro, E.; Umehara, O.; Assis, R. A.; Martins, N. E.; Gonçalves, L. C. B. (2000). Avaliação da resposta de antitoxinas beta e épsilon de Clostridium perfringens induzidas em bovinos e coelhos por seis vacinas comerciais no Brasil. Arquivo Brasileiro de Medicina Veterinária e Zootecnia. 52 (4): 313-318. doi: 10.1590/S0102-09352000000400004

Lobato, F. C. F.; Salvarani, F. M.; Gonçalves, L. A.; Pires, P. S.; Silva, R. O. S.; Alves, G. G.; Pereira, P. L. L. (2013). Clostridioses dos animais de produção. Veterinaria e zootecnia. 20: 29-48.

Manteca, C.; Daube, G.; Jauniaux, T.; Linden, A.; Pirson, V.; Detilleux, J.; Ginter, A.; Coppe, P.; Kaeckenbeeck, A.; Mainil, J. G. (2002). A role for the Clostridium perfringens beta2 toxin in bovine enterotoxaemia? Veterinary microbiology. 86: 191-202. doi: 10.1016/s0378-1135(02)00008-1

Mehdizadeh-Gohari, I.; Navarro, M. A.; Li, J.; Shrestha, A.; Uzal, F.; McClane, B. A. (2021). Pathogenicity and virulence of Clostridium perfringens. Virulence. 12: 723-753. doi: 10.1080/21505594.2021.1886777

Miclard, J.; Jäggi, M.; Sutter, E.; Wyder, M.; Grabscheid, B.; Posthaus, H. (2009a). Clostridium perfringens beta-toxin targets endothelial cells in necrotizing enteritis in piglets. Veterinary Microbiology. 137: 320-325. doi: 10.1016/j.vetmic.2009.01.025

Miclard, J.; Van-Baarlen, J.; Wyder, M.; Grabscheid, B.; Posthaus, H. (2009b). Clostridium perfringens β-toxin binding to vascular endothelial cells in a human case of enteritis necroticans. Journal of Medical Microbiology. 58: 826-828. doi: 10.1099/jmm.0.008060-0

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. Microbiology and Immunology. 41: 527-535. doi: 10.1111/j.1348-0421.1997.tb01888.x

Miyashiro, S.; Baldassi, L.; Nassar, A. (2009). Genotyping of Clostridium perfringens associated with sudden death in cattle. Journal of Venomous Animals and Toxins including Tropical Diseases. 15: 12-14. doi: 10.1590/S1678-91992009000300010

Moreira, G. M. S. G.; Salvarani, F. M.; Da-Cunha, C. E. P.; Mendonça, M.; Moreira, Â. N.; Gonçalves, L. A.; Conceição, F. R. (2016). Immunogenicity of a trivalent recombinant vaccine against Clostridium perfringens alpha, beta, and epsilon toxins in farm ruminants. Scientific reports. 6 (1): 1-9. doi: 10.1038/srep22816

Nagahama, M.; Nagayasu, K.; Kobayashi, K.; Sakurai, J. (2002). Binding component of Clostridium perfringens iota-toxin induces endocytosis in vero cells. Infection and Immunity. 70: 1909-1914. doi: 10.1128/IAI.70.4.1909-1914.2002

Nagahama, M.; Sakaguchi, Y.; Kobayashi, K.; Ochi, S.; Sakurai, J. (2000). Characterization of the enzymatic component of Clostridium perfringens iota-toxin. Journal of Bacteriology. 182: 2096-2103. doi: 10.1128/JB.182.8.2096-2103.2000

Nagahama, M.; Umezaki, M.; Tashiro, R.; Oda, M.; Kobayashi, K.; Shibutani, M.; Takagishi, T.; Ishidoh, K.; Fukuda, M.; Sakurai, J. (2012). Intracellular trafficking of Clostridium perfringens iota-toxin b. Infection and Immunity. 80: 3410-3416. doi: 10.1128/IAI.00483-12

Navarro, M. A.; McClane, B. A.; Uzal, F. A. (2018). Mechanisms of action and cell death associated with Clostridium perfringens toxins. Toxins. 10: 1-21. doi: 10.3390/toxins10050212

Navarro, M. A.; Shrestha, A.; Freedman, J. C.; Beingesser, J.; McClane, B. A.; Uzal, F. A. (2019). Potential therapeutic effects of mepacrine against clostridium perfringens enterotoxin in a mouse model of enterotoxemia. Infection and Immunity. 87: 1-10. doi: 10.1128/IAI.00670-18

Park, M.; Deck, J.; Foley, S. L.; Nayak, R.; Songer, J. G.; Seibel, J. R.; Rafii, F. (2016). Diversity of Clostridium perfringens isolates from various sources and prevalence of conjugative plasmids. Anaerobe. 38: 25-35. doi: 10.1016/j.anaerobe.2015.11.003

Perelle, S.; Domenighini, M.; Popoff, M. R. (1996). Evidence that Arg-295, Glu-378, and Glu-380 are active-site residues of the ADP-ribosyltransferase activity of iota toxin. FEBS Letters. 395: 191-194. doi: 10.1016/0014-5793(96)01035-6

Prescott, J. F.; Parreira, V. R.; Mehdizadeh-Gohari, I.; Lepp, D.; Gong, J. (2016). The pathogenesis of necrotic enteritis in chickens: what we know and what we need to know: a review. Avian Pathology. 45: 288-294. doi: 10.1080/03079457.2016.1139688

Redondo, L. M.; Carrasco, J. M. D.; Redondo, E. A.; Delgado, F.; Fernández-Miyakawa, M. E. (2015). Clostridium perfringens type E virulence traits involved in gut colonization. PLoS ONE. 10: 1-18. doi: 10.1371/journal.pone.0121305

Redondo, L. M.; Farber, M.; Venzano, A.; Jost, B. H.; Parma, Y. R.; Fernandez-Miyakawa, M. E. (2013). Sudden death syndrome in adult cows associated with Clostridium perfringens type E. Anaerobe. 20: 1-4. doi: 10.1016/j.anaerobe.2013.01.001

Redondo, L. M.; Redondo, E. A.; Dailoff, G. C.; Leiva, C. L.; Diaz-Carrasco, J. M.; Bruzzone, O. A.; Cangelosi, A.; Geoghegan, P.; Fernandez-Miyakawa, M. E. (2017). Effects of Clostridium perfringens iota toxin in the small intestine of mice. Anaerobe. 48: 83-88. doi: 10.1016/j.anaerobe.2017.07.007

Richard, J. F.; Mainguy, G.; Gibert, M.; Marvaud, J. C.; Stiles, B. G.; Popoff, M. R. (2002). Transcytosis of iota-toxin across polarized CaCo-2 cells. Molecular Microbiology. 43: 907-917. doi: 10.1046/j.1365-2958.2002.02806.x

Rood, J. I.; Adams, V.; Lacey, J.; Lyras, D.; McClane, B. A.; Melville, S. B.; Moore, R. J.; Popoff, M. R.; Sarker, M. R.; Songer, J. G.; Uzal, F. A.; Van-Immerseel, F. (2018). Expansion of the Clostridium perfringens toxin-based typing scheme. Anaerobe. 53: 5-10. doi: 10.1016/j.anaerobe.2018.04.011

Rood, J. I.; Keyburn, A. L.; Moore, R. J. (2016). NetB and necrotic enteritis: the hole movable story. Avian Pathology. 45: 295-301. doi: 10.1080/03079457.2016.1158781

Sakurai, J.; Nagahama, M.; Oda, M.; Tsuge, H.; Kobayashi, K. (2009). Clostridium perfringens iota-toxin: structure and function. Toxins. 1: 208-228. doi: 10.3390/toxins1020208

Santana, J. A.; Ferreira, A. C. D. A.; Souza, M. D. C. C. D.; Moreira, M. A. S.; Lima, M. C.; Cruz, D. S. G.; Lobato, F. C. F.; Silva, R. O. S. (2018). Isolation and genotyping of clostridium perfringens from goats in Minas Gerais, Brazil. Ciencia Rural. 48: 5-8. doi: 10.1590/0103-8478cr20180101

Sari, R. S.; Almeida, A. C.; Cangussu, A. S. R.; Jorge, E. V.; Mozzer, D. O.; Santos, H. O.; Quintilio, W.; Brandi, I. V.; Andrade, V. A.; Miguel, A. S. M.; Santos, E. M. S. (2016). Anti-botulism single-shot vaccine using chitosan for protein encapsulation by simple coacervation. Anaerobe. 42: 182-187.

Sayeed, S.; Uzal, F. A.; Fisher, D. J.; Saputo, J.; Vidal, J. E.; Chen, Y., Gupta, P.; Rood, J. I.; McClane, B. A. (2008). Beta toxin is essential for the intestinal virulence of Clostridium perfringens type C disease isolate CN3685 in a rabbit ileal loop model. Molecular Microbiology. 67: 15-30. doi: 10.1111/j.1365-2958.2007.06007.x

Schmidt, G.; Papatheodorou, P.; Aktories, K. (2015). Novel receptors for bacterial protein toxins. Current Opinion in Microbiology. 23: 55-61. doi: 10.1016/j.mib.2014.11.003

Schumacher, V. L.; Martel, A.; Pasmans, F.; van-Immerseel, F.; Posthaus, H. (2013). Endothelial binding of beta toxin to small intestinal mucosal endothelial cells in early stages of experimentally induced Clostridium perfringens type C enteritis in pigs. Veterinary Pathology. 50: 626-629. doi: 10.1177/0300985812461362

Shrestha, A.; Uzal, F. A.; McClane, B. A. (2019). Enterotoxic Clostridia: Clostridium perfringens Enteric Diseases. Gram-Positive Pathogens. 6: 977-990. doi: 10.1128/9781683670131.ch60

Silva, R. O. S.; Lobato, F. C. F. (2015). Clostridium perfringens: A review of enteric diseases in dogs, cats and wild animals. Anaerobe. 33: 14-17. doi: 10.1016/j.anaerobe.2015.01.006

Silva, R. O. S.; Oliveira-Junior, C. A.; Guedes, R. M. C.; Lobato, F. C. F. (2015). Clostridium perfringens: a review of the disease in pigs, horses and broiler chickens. Ciência Rural. 45: 1027-1034. doi: 10.1590/0103-8478cr20140927

Simpson, K. M.; Callan, R. J.; Van-Metre, D. C. (2018). Clostridial Abomasitis and Enteritis in Ruminants. Veterinary Clinics of North America: Food Animal Practice. 34: 155-184. doi: 10.1016/j.cvfa.2017.10.010

Smedley, J. G.; McClane, B. A. (2004). Fine mapping of the N-terminal cytotoxicity region of Clostridium perfringens enterotoxin by site-directed mutagenesis. Infection and Immunity. 72: 6914-6923. doi: 10.1128/IAI.72.12.6914-6923.2004

Sobrinho, E. M.; Almeida, A. C.; Brandi, I. V.; Colen, F.; Lobato, F. C. F.; Cangussu, A. S. R.; Quintilio, W.; Santos, H. O.; Sari, R. S. (2014). ELISA and modified toxin-binding inhibition test for quality control of the clostridial vaccine processes. Arquivo Brasileiro de Medicina Veterinaria e Zootecnia. 66: 713-720. doi: 10.1590/1678-41625407

Sobrinho, E. M.; Cangussu, A. S. R.; Brandi, I. V.; Sari, R. S.; Almeida, A. C.; Colen,F.; Quintilio, W.; Santos, H. O. (2010). Modified toxin-binding inhibition (ToBI) test for epsilon antitoxin determination in serum of immunized rabbits. Veterinary Immunology and Immunopathology. 138: 129-133. doi: 10.1016/j.vetimm.2010.07.007

Songer, J. G. (1996). Clostridial enteric diseases of domestic animals. Clinical Microbiology Reviews. 9: 216-234. doi: 10.1128/cmr.9.2.216

Songer, J. G.; Miskimmins, D. W. (2004). Clostridium perfringens type E enteritis in calves: Two cases and a brief review of the literature. Anaerobe. 10: 239-242. doi: 10.1016/j.anaerobe.2004.05.001

Stiles, B. G.; Wilkins, T. D. (1986). Purification and characterization of Clostridium perfringens iota toxin: Dependence on two nonlinked proteins for biological activity. Infection and Immunity. 54: 683-688. doi: 10.1128/iai.54.3.683-688.1986

Szklarczyk D, Gable A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; Doncheva, N.T.; Legeay, M.; Fang, T.; Bork, P.; Jensen, L.J.; von Mering, C. (2021). The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021 Jan 8;49(D1):D605-12

Takahashi, A.; Komiya, E.; Kakutani, H.; Yoshida, T.; Fujii, M.; Horiguchi, Y.; Mizuguchi, H.; Tsutsumi, Y.; ichi-Tsunoda, S.; Koizumi, N.; Isoda, K.; Yagi, K.; Watanabe, Y.; Kondoh, M. (2008). Domain mapping of a claudin-4 modulator, the C-terminal region of C-terminal fragment of Clostridium perfringens enterotoxin, by site-directed mutagenesis. Biochemical Pharmacology. 75: 1639-1648. doi: 10.1016/j.bcp.2007.12.016

Takehara, M.; Takagishi, T.; Seike, S.; Oda, M.; Sakaguchi, Y.; Hisatsune, J.; Ochi, S.; Kobayashi, K.; Nagahama, M. (2017). Cellular entry of Clostridium perfringens iota-toxin and Clostridium botulinum C2 toxin. Toxins. 9: 8-11. doi: 10.3390/toxins9080247

Tsuge, H.; Nagahama, M.; Nishimura, H.; Hisatsune, J.; Sakaguchi, Y.; Itogawa, Y.; Katunuma, N.; Sakurai, J. (2003). Crystal structure and site-directed mutagenesis of enzymatic components from Clostridium perfringens Iota-toxin. Journal of Molecular Biology. 325: 471-483. doi: 10.1016/S0022-2836(02)01247-0

Tsuge, H.; Nagahama, M.; Oda, M.; Iwamoto, S.; Utsunomiya, H.; Marquez, V. E.; Katunuma, N.; Nishizawa, M.; Sakurai, J. (2008). Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens ι-toxin. Proceedings of the National Academy of Sciences of the United States of America. 105: 7399-7404. doi: 10.1073/pnas.0801215105

Uzal, F. A. (2004). Diagnosis of Clostridium perfringens intestinal infections in sheep and goats. Anaerobe. 10: 135-143. doi: 10.1016/j.anaerobe.2003.08.005

Uzal, F. A.; Kelly, W. R. (1997). Effects of the intravenous administration of Clostridium perfringens type D epsilon toxin on young goats and lambs. Journal of Comparative Pathology. 116: 63-71. doi: 10.1016/S0021-9975(97)80044-8

Uzal, F. A.; Navarro, M. A.; Li, J.; Freedman, J. C.; Shrestha, A.; McClane, B. A. (2018). Comparative pathogenesis of enteric clostridial infections in humans and animals. Anaerobe. 53: 11-20. doi: 10.1016/j.anaerobe.2018.06.002

Uzal, F. A.; Sentíes-Cué, C. G.; Rimoldi, G.; Shivaprasad, H. L. (2016). Non- Clostridium perfringens infectious agents producing necrotic enteritis-like lesions in poultry. Avian Pathology. 45: 326-333. doi: 10.1080/03079457.2016.1159282

Uzal, F. A.; Vidal, J. E.; McClane, B. A.; Gurjar, A. A. (2010). Clostridium Perfringens Toxins Involved in Mammalian Veterinary Diseases. The open toxinology journal. 2: 24-42. doi: 10.2174/1875414701003010024

Van Itallie, C. M.; Betts, L.; Smedley, J. G.; McClane, B. A.; Anderson, J. M. (2008). Structure of the Claudin-binding domain of Clostridium perfringens enterotoxin. Journal of Biological Chemistry. 283: 268-274. doi: 10.1074/jbc.M708066200

Vidal, J. E.; Ohtani, K.; Shimizu, T.; McClane, B. A. (2009). Contact with enterocyte-like Caco-2 cells induces rapid upregulation of toxin production by Clostridium perfringens type C isolates. Cellular Microbiology. 11: 1306-1328. doi: 10.1111/j.1462-5822.2009.01332.x

Waters, M.; Raju, D.; Garmory, H. S.; Popoff, M. R.; Sarker, M. R. (2005). Regulated expression of the beta2-toxin gene (cpb2) in Clostridium perfringens type A isolates from horses with gastrointestinal diseases. Journal of Clinical Microbiology. 43: 4002-4009. doi: 10.1128/JCM.43.8.4002-4009.2005

Wigelsworth, D. J.; Ruthel, G.; Schnell, L.; Herrlich, P.; Blonder, J.; Veenstra, T. D.; Carman, R. J.; Wilkins, T. D.; Van-Nhieu, G. T.; Pauillac, S.; Gibert, M.; Sauvonnet, N.; Stiles, B. G.; Popoff, M. R.; Barth, H. (2012). CD44 Promotes Intoxication by the Clostridial Iota-Family Toxins. PLoS ONE. 7: e51356. doi: 10.1371/journal.pone.0051356

Yamada, T.; Yoshida, T.; Kawamoto, A.; Mitsuoka, K.; Iwasaki, K.; Tsuge, H. (2020). Cryo-EM structures reveal translocational unfolding in the clostridial binary iota toxin complex. Nature Structural & Molecular Biology. 27: 288-296. doi: 10.1038/s41594-020-0388-6

How to Cite
Brito, H., Alencar, F., Albuquerque, B., Silva, M., Felix, M., Mulholland, D., Oliveira, E., Mariúba, L. A., Sobrinho, E., Brandi, I., Lobato, F. C., & Cangussu, A. S. (2021). Pathologic findings on ruminant enteric clostridial diseases reveal specificities and differences among iota and iota-like toxins. Revista De Ciencias Agrícolas, 38(2), 157-174.