Cholera pp 199-208 | Cite as


  • Jan Holmgren
Part of the Current Topics in Infectious Disease book series (CTID)


The pathogenesis of cholera is intimately associated with the production and action of the enterotoxin molecule known as cholera toxin (in earlier work sometimes called choleragen or permeability factor) by the cholera vibrios. It is now 20 years since experimental evidence first clearly suggested that cholera is a toxin-mediated disease. Robert Koch, who identified V. cholerae as the causative agent of cholera, had already proposed in 1884 that the disease was toxin-mediated1 but it was not until 1959 that the Indian scientists De2 and Dutta3 and their co-workers convincingly demonstrated the existence of the cholera toxin. Today, cholera is recognized as the prototype of a large group of diarrheal diseases that are also mediated by enterotoxins, some of which are structurally and functionally related to the cholera enterotoxin. Collectively, these other “enterotoxic enteropathies”4 are more important than cholera as causes of morbidity and mortality in most parts of the world. Still, however, the main information about the pathogenesis of this whole group of diseases was derived from basic research about the pathogenesis of cholera and to a large extent to specific studies of the cholera toxin molecule and its mode of action.


Adenylate Cyclase Cholera Toxin Vasoactive Intestinal Polypeptide Enteric Nervous System Intestinal Epithelial Cell Line 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Koch R: An address on cholera and its bacillus. Br Med J (August 30): 403–407; 453-459, 1884.Google Scholar
  2. 2.
    De SN: Enterotoxicity of bacteria-free culture-filtrate of Vibrio cholerae. Nature (London) 183: 1533–1534, 1959.CrossRefGoogle Scholar
  3. 3.
    Dutta NK, Panse MV, Kulkarni DR: Role of cholera toxin in experimental cholera. J Bact 78: 594–595, 1959.PubMedGoogle Scholar
  4. 4.
    Craig JP: A survey of the enterotoxic enteropathies, in Ouchterlony Ö, Holmgren J, (eds): Cholera and Related Diarrheas. 43rd Nobel Symposium, Stockholm 1978. Basel, Karger, 1980, p 15.Google Scholar
  5. 5.
    Holmgren J: Actions of cholera toxin and the prevention and treatment of cholera. Nature 292: 413–417, 1981.PubMedCrossRefGoogle Scholar
  6. 6.
    Lai C-Y: The chemistry and biology of cholera toxin. CRC Crit Rev Biochem. 9: 171–206, 1980.PubMedCrossRefGoogle Scholar
  7. 7.
    Moss J, Vaughan M: Activation of adenylate cyclase by choleragen. A Rev Biochem 48: 581–600, 1979.CrossRefGoogle Scholar
  8. 8.
    Gill DM: The arrangement of subunits in cholera toxin. Biochemistry NY 15: 1242–1248, 1976.CrossRefGoogle Scholar
  9. 9.
    Lönnroth I, Holmgren J: Subunit structure of cholera toxin. J Gen Microbiol 76: 417–427, 1973.PubMedCrossRefGoogle Scholar
  10. 10.
    Holmgren J, Lindholm L, Lönnroth I: Interaction of cholera toxin and toxin derivatives with lymphocytes. I. Binding properties and interference with lectin-induced cellular stimulation. J Exp Med 139: 801–819, 1974.PubMedCrossRefGoogle Scholar
  11. 11.
    Gill DM, King CA: The mechanism of action of cholera toxin in pigeon erythrocyte lysates. J Biol Chem 424-432, 1975.Google Scholar
  12. 12.
    Mekalanos JJ, Swartz DJ, Pearson GDN, Harford N, Groyne F, DeWilde M: Cholera toxin gene: nucleotide sequence, deletion analysis and vaccine development. Nature (London) 306: 551–557, 1983.CrossRefGoogle Scholar
  13. 13.
    Miller VL, Mekelanos JJ: Synthesis of cholera toxin is positively regulated at the transcriptional level by toxR. Proc Natl Acad Sci USA 81: 3471–3475, 1984.PubMedCrossRefGoogle Scholar
  14. 14.
    Taylor RK, Miller VL, Furlong DB, Mekelanos JJ: The use of PhoA gene fusions to identify pilus colonization factor coordinately regulated with cholera toxin. Proc Natl Acad Sci USA, 84: 2833–2837, 1987.PubMedCrossRefGoogle Scholar
  15. 15.
    Palva ET, Hirst TR, Hardy SJS, Holmgren J, Randall, L: Synthesis of precursors to the B subunit of heat-labile enterotoxin in Escherichia coli. J Bacteriol 146: 325–339, 1981.PubMedGoogle Scholar
  16. 16.
    Hirst TR, Sanchez J, Kaper JB, Hardy SJS, Holmgren J: Mechanisms of toxin secretion by Vibrio cholerae investigated in strains harboring plasmids that encode heat-labile enterotoxins of Escherichia coli. Proc Natl Acad Sci USA 81: 7752–7756, 1984.PubMedCrossRefGoogle Scholar
  17. 17.
    Hirst TR, Holmgren J: Transient entry of enterotoxin subunits into the periplasm during their secretion from Vibrio cholerae. J Bacteriol 169: 1037–1045, 1987.PubMedGoogle Scholar
  18. 18.
    Hirst TR, Holmgren J: Conformation and protein secreted across bacterial outer membranes: A study of enterotoxin translocation from Vibrio cholerae. Proc Natl Acad Sci USA 84: 7418–7422, 1987.PubMedCrossRefGoogle Scholar
  19. 19.
    Hardy SJS, Holmgren J, Johansson S, Sanchez J & Hirst TR: Coordinated assembly of multisubunit proteins: Oligomerization of bacterial enterotoxins in vivo and in vitro. Proc Natl Acad Sci USA 85: 7109–7113, 1988.PubMedCrossRefGoogle Scholar
  20. 20.
    Cuatrecasas P: Interaction of Vibrio cholerae enterotoxin with cell membranes. Biochemistry NY 12: 3547–3558, 1973.CrossRefGoogle Scholar
  21. 21.
    Holmgren J, Lönnroth I, Månsson JE, Svennerholm L: Interaction of cholera toxin and membrane GM1 ganglioside of small intestine. Proc Natl Acad Sci USA 72: 2520–2524, 1975.PubMedCrossRefGoogle Scholar
  22. 22.
    Heyningen WE van, Carpenter CCJ, Pierce NF, Greenough WB: Deactivation of cholera toxin by ganglioside GM1. Science 183: 656–657, 1974.CrossRefGoogle Scholar
  23. 23.
    Holmgren J, Lönnroth I, Svennerholm L: Tissue receptor for cholera exotoxin: postulated structure studies with GM1 ganglioside and related glycolipids. Infect Immun 8: 208–214, 1973.PubMedGoogle Scholar
  24. 24.
    Cuatrecasas P: Gangliosides and membrane receptors for cholera toxin. Biochemistry NY 12: 3558–3566, 1973.CrossRefGoogle Scholar
  25. 25.
    King CA, van Heyningen WE: Deactivation of cholera toxin by a sialidase-resistant monosialosylganglioside. J Infect Dis 127: 639–647, 1973.PubMedCrossRefGoogle Scholar
  26. 26.
    Fishman PH: Internalization and degradation of cholera toxin by cultured cells: relationship to toxin action. J Cell Biol 93: 860–865, 1982.PubMedCrossRefGoogle Scholar
  27. 27.
    Moss J, Vaughan M: Mechanism of action of choleragen. Evidence for ADP-ribosyl transferase activity with arginine as an acceptor. J Biol Chem, 252: 2455–2457, 1977.PubMedGoogle Scholar
  28. 28.
    Pfeuffer T, Cassel D: Mechanism of cholera action: covalent modification of the guanyl nucleotide-binding protein of the adenylate cyclase system. Proc Natl Acad Sci USA 75: 2669–2673, 1978.PubMedCrossRefGoogle Scholar
  29. 29.
    Cassel D, Selinger Z: Mechanisms of adenylate cyclase activation by cholera toxin: inhibition of GTP hydrolysis at the regulatory site. Proc Natl Acad Sci USA 74: 3307–3311, 1977.PubMedCrossRefGoogle Scholar
  30. 30.
    Field M: Regulation of small intestine ion transport by cyclic nucleotides and calcium, in Field M, Fordtran JS, Schultz SG, (eds): Secretory Diarrhea. Bethesda, MD, American Physiology Society, 1980, p 21.Google Scholar
  31. 31.
    Powell DW, Berschneider HM, Lawson LD, Marens H: Regulation of water and ion movement in intestine, in Microbial Toxins and Diarrheal Disease, London, Pitman, (CIBA Foundation Symposium 112), 1985 p 14.Google Scholar
  32. 32.
    Turnberg LA: Mechanisms of intestinal absorption and secretion of electrolytes and water, in Holmgren J, Lindberg A, Möllby R (eds): Development of Vaccines and Drugs against Diarrhea. 11th Nobel Conference Stockholm 1985. Lund, Sweden, Studentlitteratur, 1986, p 231.Google Scholar
  33. 33.
    Carpenter CCJ, Sack RB, Feeley JC, Steenberg RW: Site and characteristics of electrolyte loss and effect of intraluminal glucose in experimental canine cholera. J Clin Invest 47: 1210–1220, 1968.PubMedCrossRefGoogle Scholar
  34. 34.
    Banwell JG, Pierce NF, Mitra RC, Brigham K, Caranasos GJ, Keimowitz RI, Redson DS, Thomas J, Gorbach SL, Sack RB, Mondai A: Intestinal fluid and electrolyte transport in human cholera. J Clin Invest 49: 183–195, 1970.PubMedCrossRefGoogle Scholar
  35. 35.
    Carpenter CCJ, Greenough WB III: Response of the canine duodenum to intraluminal challenge with cholera exotoxin. J Clin Invest 47: 2600–2607, 1968.PubMedCrossRefGoogle Scholar
  36. 36.
    Field M, Fromm D, Wallace CK, Greenough WB: Stimulation of active chloride secretion in small intestine by cholera exotoxin. J Clin Invest. 48: 24a, 1969.Google Scholar
  37. 37.
    De Jonge HR, Lohmann SM: Mechanisms by which cyclic nucleotides and other intracellular mediators regulate secretion, in Microbial Toxins and Diarrheal Disease, London, Pitman, (CIBA Foundation Symposium 112), p 116, 1985.Google Scholar
  38. 38.
    Dharmaathaphorn K, McRoberts JA, Mandai KG, Tisdale LO, Masui H: A human colonie tumor cell line that maintains vectorial electrolyte transport. Am J Physiol 246: G204–G208, 1984.Google Scholar
  39. 39.
    Jodal M, Lundgren O: Enterotoxin-induced fluid secretion and the enteric nervous system, in Holmgren J, Lindberg A, Möllby R (eds), Development of Vaccines and Drugs against Diarrhea. 11th Nobel Conference, Stockholm 1985. Lund, Sweden, Studentlitteratur, 1986, p 278.Google Scholar
  40. 40.
    Mathias JR, Carlson GM, DiMarino AJ, Bertiger G, Morton HE, Cohen S: Intestinal myoelectric activity in response to live Vibrio cholerae and cholera enterotoxin. J Clin Invest 58: 91–96, 1976.PubMedCrossRefGoogle Scholar
  41. 41.
    Kaper JB, Lockman H, Baldini MM, Levine MM: Recombinant nontoxinogenic Vibrio cholerae strains as attenuated cholera vaccine candidates. Nature (London) 308: 655–658, 1984.CrossRefGoogle Scholar
  42. 42.
    Honda T, Finkelstein RA: Purification and characterization of the hemolysin produced by Vibrio cholerae biotype El Tor: Another toxic substance produced by cholera vibrios. Infect Immun 26: 1020–1027, 1979.PubMedGoogle Scholar
  43. 43.
    O’Brien AD, Chen MI, Holmes RK, Kaper J, Levine MM: Environmental and human isolates of Vibrio cholerae and Vibrio parahemolyticus produce a Shigella dysenteriae 1 (Shiga)-like cytotoxin. Lancet i: 77–78, 1984.CrossRefGoogle Scholar
  44. 44.
    Svennerholm A-M, Strömberg Jonson G, Holmgren J: Vibrio cholerae soluble hemagglutinin: purification and development of ELISA methods for antigen and antibody quantitations. Infect Immun 41: 237–243, 1983.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Jan Holmgren

There are no affiliations available

Personalised recommendations