Chapter 14 : Bacteriophages Encoding Botulinum and Diphtheria Toxins

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Bacteriophages Encoding Botulinum and Diphtheria Toxins, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816506/9781555813079_Chap14-1.gif /docserver/preview/fulltext/10.1128/9781555816506/9781555813079_Chap14-2.gif


Bacteriophages have long been recognized to harbor genes that encode various classes of virulence factors, including protein toxins. Some classic examples of phage conversion of grampositive hosts to toxinogenesis are the production of diphtheria toxin (DT) in and the production of botulinum neurotoxins (BoNTs) in types C and D of . DT has generally been considered mainly responsible for the gross symptoms of diphtheria, and the lack of genetic systems for has prevented the identification of other virulence factors associated with its pathogenicity. The association of DT with phages provides a classic example of lysogenic conversion, whereby the bacterial cell acquires traits as a consequence of phage infection. has attracted much interest in recent years, largely due to advances in the study of the structure, function, and genetics of the neurotoxins it encodes and in the therapeutic applications of these toxins for the treatment of several neurologic disorders. BoNTs and tetanus neurotoxin (TeNT) act by selectively blocking the neurotransmission of presynaptic nerve terminals in the peripheral and central nervous systems. The characterization of genes for BoNT and associated proteins of the toxin complexes indicated that these genes are located on the chromosome, on pseudolysogenic bacteriophages, or on plasmids, depending on the serotype. Converting and nonconverting phages from types C and D have been isolated and partially characterized.

Citation: Johnson E. 2005. Bacteriophages Encoding Botulinum and Diphtheria Toxins, p 280-296. In Waldor M, Friedman D, Adhya S (ed), Phages. ASM Press, Washington, DC. doi: 10.1128/9781555816506.ch14

Key Concept Ranking

Circular Double-Stranded DNA
Linear Double-Stranded DNA
Bacterial Virulence Factors
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Relationships of bacteriophages and toxins produced by types C and D. Adapted from reference with permission of the publisher.

Citation: Johnson E. 2005. Bacteriophages Encoding Botulinum and Diphtheria Toxins, p 280-296. In Waldor M, Friedman D, Adhya S (ed), Phages. ASM Press, Washington, DC. doi: 10.1128/9781555816506.ch14
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Adams, M. H. 1959. Bacteriophages. Wiley Interscience, New York, N.Y.
2. Anderson, N. G. 1970. Evolutionary significance of virus infection. Nature 207:13461347.
3. Arnon, S. S.,, R. Schechter,, T. H. Inglesby,, D. A. Henderson,, J. G. Bartlett,, M. S. Ascher,, E. Eitzen,, A. D. Fine,, J. Hauer,, J. Layton,, S. Lillibridge,, M. T. Osterholm,, T. O’Toole,, G. Parker,, T. M. Perl,, P. K. Russell,, D. L. Swerdlow,, and K. Tonat for the Working Group on Civilian Biodefense. 2001. Botulinum toxin as a biological weapon. Medical and public health management. JAMA 285:10591070.
4. Barksdale, L. 1959. Lysogenic conversion in bacteria. Bacteriol. Rev. 23:202212.
5. Barksdale, L. 1970. Corynebacterium diphtheriae and its relatives. Bacteriol. Rev. 34:378422.
6.Barksdale L. 1971. The gene, tox+, of Corynebacterium diphtheriae, p. 215232. In J. Monod, and E. Borek (ed.), Of Microbes and Life. Columbia University Press, New York, N. Y.
7. Barksdale, L,, and S. B. Arden. Persisting bacteriophage infections, lysogeny, and phage conversions. Annu. Rev. Microbiol. 28:265269.
8. Barksdale, W. L.,, and A. M. Pappenheimer, Jr. 1954. Phage-host relationships in toxigenic and nontoxigenic diphtheria bacilli. J. Bacteriol. 67:220232.
9. Barondess, J. J.,, and J. Beckwith. 1990. A bacterial virulence determinant encoded by lysogenic coliphage λ. Nature 346:871873.
10. Betz, J. V. 1968. Some properties of bacteriophages active on the obligate anaerobe Clostridium sporogenes. Virology 36:919.
11. Bishai, W. R.,, and J. R. Murphy,. 1988. Bacteriophage gene products that cause human disease, p. 683724. In R. Calendar (ed.), the Bacteriophages, vol. 2. Plenum Press, New York, N.Y.
12. Brock, T. D. 1990. The Emergence of Bacterial Genetics. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
13. Buck, G. A.,, R. E. Cross,, T. P. Wong,, J. Loera,, and N. Groman. 1985. DNA relationships among some tox-bearing cornynebacteriophages. Infect. Immun. 49:679684.
14. Burgi, E.,, and A. D. Hershey. 1963. Sedimentation rate as a measure of molecular weight of DNA. Biophys. J. 3:309321.
15. Campbell, A. M. 1992. Chromosomal insertion sites for phages and plasmids. J. Bacteriol. 174:74967499.
16. Canchaya, C.,, G. Fournous,, S. Chibani-Chennoufi,, M.-L. Dillman,, and H. Brüssow. 2003. Phages as agents of lateral gene transfer. Curr. Opin. Microbiol. 6:417424.
17. Canchaya, C.,, C. Proux,, G. Fournous,, A. Bruttin,, and H. Brüssow. 2003. Prophage genomics. Microbiol. Mol. Biol. Rev. 67:238276.
18. Casjens, S. 2003. Prophages and bacterial genomics: what have we learned so far? Mol. Microbiol. 49:277300.
19. Cerdeño-Tárraga, A. M.,, A. Efstratiou,, L. G. Dover,, M. T. G. Holden,, M. Pallen,, S. D. Bentley,, G. S. Besra,, C. Churcher,, K. D. James,, A. De Zoysa,, T. Chillingworth,, A. Cronin,, L. Dowd,, T. Feltwell,, N. Hamlin,, S. Holroyd,, K. Jagels,, S. Moule,, M. A. Quail,, E. Rabbinowotsch,, K. M. Rutherford,, N. R. Thompson,, L. Unwin,, S. Whitehead,, B. G. Barrell,, and J. Parkhill. 2003. The complete genome sequence and analysis of Corynebacterium diphtheriae NCTC13129. Nucleic Acids Res. 31:65166523.
20. Cheetham, B. F.,, and M. E. Katz. 1995. A role for bacteriophages in the evolution and transfer of bacterial virulence determinants. Mol. Microbiol. 18:201208.
21. Cianciotto, N. P.,, and N. B. Groman. 1996. Extended host range of a β-related corynebacteriophage. FEMS Microbiol. Lett. 140:221225.
22. Collier, R. J. 1975. Diphtheria toxin: mode of action and structure. Bacteriol. Rev. 39:5485.
23. Collier, R. J. 2001. Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century. Toxicon 39:17931803.
24. Dolman, C. E.,, and E. Chang. 1972. Bacteriophages of Clostridium botulinum. Can. J. Microbiol. 18:6776.
25. Eklund, M. W.,, F. T. Poysky,, and E. S. Boatman. 1969. Bacteriophages of Clostridium botulinum types A, b, E, and F and nontoxigenic strains resembling type E. J. Virol. 3:270274.
26. Eklund, M. W.,, F. T. Poysky,, and W. H. Habig,. 1989. Bacteriophages and plasmids in Clostridium botulinum and Clostridium tetani and their relationship to production of toxins, p. 2551. In L. L. Simpson (ed.), Botulinum Neurotoxin and Tetanus Toxin. Academic Press, San Diego, Calif.
27. Eklund, M. W.,, F. T. Poysky,, S. M. Reed,, and C. A. Smith. 1971. Bacteriophage and toxigenicity of Clostridium botulinum type C. Science 172:480482.
28. Eklund, M. W.,, F. T. Poysky,, and S. M. Reed. 1972. Bacteriophages and the toxigenicity of Clostridium botulinum type D. Nat. New Biol. 235:1617.
29. Eklund, M. W.,, and F. T. Poysky. 1974. Interconversion of types C and D strains of Clostridium botulinum by specific bacteriophages. Appl. Microbiol. 27:251258.
30. Eklund, M. W.,, F. T. Poysky,, J. A. Meyers,, and G. A. Pelroy. 1974. Interspecies conversion of Clostridium botulinum type C to Clostridium novyi by bacteriophage. Science 186:456458.
31. Eklund, M. W.,, L. Poysky,, M. Mseiteif,, and M. S. Strom. 1988. Evidence for plasmid-mediated toxin and bacteriocin production in Clostridium botulinum type G. Appl. Environ. Microbiol. 54:14051408.
32. Franciosa, G.,, J. L. Ferreira,, and C. L. Hatheway. 1994. Detection of type A, b, and E botulism neurotoxin genes in Clostridium botulinum and other Clostridium species by PCR: evidence of unexpressed type B toxin genes in type A toxigenic organisms. J. Clin. Microbiol. 32:19111917.
33. Freeman, V. J. 1951. Studies on the virulence of bacteriophage-infected strains of Corynebacterium diphtheriae. J. Bacteriol. 63:675688.
34. Freeman, V. J.,, and I. U. Morse. 1952. Further observations on the change to virulence of bacteriophage- infected avirulent strains of Corynebacterium diphtheriae. J. Bacteriol. 63:407414.
35. Friedman, D. I.,, and D. L. Court. 2001. Bacteriophage lambda: alive and well and still doing its thing. Curr. Opin. Microbiol. 4:201207.
36. Fujinaga, Y.,, K. Inoue,, S. Shimazaki,, K. Tomochika,, K. Tsuzuki,, N. Fujii,, T. Watanabe,, T. Ohyama,, K. Takeshi,, K. Inoue,, and K. Oguma. 1994. Molecular construction of Clostridium botulinum type C progenitor toxin and its gene organization. Biochem. Biophys. Res. Commun. 205:12911298.
37. Galazka, A. 2000. The changing epidemiology of diphtheria in the vaccine era. J. Infect. Dis. 181(Suppl. 1):S2S9.
38. Galazka, A. 2000. Implications of the diphtheria epidemic in the former Soviet Union for immunization programs. J. Infect. Dis. 18(Suppl. 1):S244S248.
39. Gentry-Weeks, P.,, S. Coburn,, and M. S. Gilmore. 2002. Phages and other mobile virulence elements in gram-positive pathogens. Curr. Top. Microbiol. Immunol. 264:7994.
40. Giannini, G.,, R. Rappuoli,, and G. Ratti. 1984. The amino acid sequence of two nontoxic mutants of diphtheria toxin CRM45 and CRM197. Nucleic Acids Res. 12:40634069.
41. Gill, D. M. 1982. Bacterial toxins: a table of lethal amounts. Bacteriol. Rev. 46:8694.
42. Gill, D. M.,, T. Uchida,, and R. A. Singer. 1972. Expression of diphtheria toxin genes carried by integrated and nonintegrated phage beta. Virology 50:664668.
43. Greenfield, L. 1992. Diphtheria toxin cloning and expression in Corynebacterium diphtheriae. Targeted Diagn. Ther. 7:273305.
44. Greenfield, L.,, M. J. Bjorn,, G. Horn,, D. Fong,, G. A. Buck,, R. J. Collier,, and D. A. Kaplan. 1983. Nucleotide sequence of the structural gene for diphtheria toxin carried by corynebacteriophage β. Proc. Natl. Acad. Sci. USA 80:68536857.
45. Groman, N. B. 1953. Evidence for the induced nature of the change from nontoxigenicity to toxigenicity in Corynebacterium diphtheriae as a result of exposure to specific bacteriophage. J. Bacteriol. 66:184191.
46. Groman, N. B. 1955. Evidence for the active role of bacteriophage in the conversion of nontoxigenic Corynebacterium diphtheriae to toxin production. J. Bacteriol. 69:615.
47. Groman, N. B.,, and M. Eaton. 1955. Genetic factors in Corynebacterium diphtheriae conversion. J. Bacteriol. 70:637640.
48. Guedon, E.,, and J. D. Helmann. 2003. Origins of metal ion selectivity in the DtxR/MntR family of metalloregulators. Mol. Microbiol. 48:495497.
49. Hacker, J.,, and J. B. Kaper. 2000. Pathogenicity islands and the evolution of microbes. Annu. Rev. Microbiol. 54:641679.
50. Hadfield, T. L.,, P. McEvoy,, Y. Polotsky,, V. A. Tzinserling,, and A. A. Yakolev. 2000. The pathology of diphtheria. J. Infect. Dis. 181(Suppl. 1):S116S120.
51. Hariharan, H.,, and W. R. Mitchell. 1976. Observations on bacteriophages of Clostridium botulinum type C isolates from different sources and the role of certain phages in toxigenicity. Appl. Environ. Microbiol. 32:145158.
52. Hatheway, C. L.,, and E. A. Johnson,. 1998. Clostridium: the spore-bearing anaerobes, p. 731782. In L. Collier,, A. Balows,, and M. Sussman (ed.), Topley andWilson’s Microbiology and Microbial Infections, 9th ed., vol. 2. Arnold, London, United Kingdom.
53. Hauser, D.,, M. W. Eklund,, P. Boquet,, and M. R. Popoff. 1994. Organization of the botulinum neurotoxin C1 gene and its associated nontoxic protein genes in Clostridium botulinum C468. Mol. Gen. Genet. 243:631640.
54. Hauser, D.,, P. Gibert,, P. Boquet,, and M. R. Popoff. 1992. Plasmid localization of a type E botulinal neurotoxin gene homologue in toxigenic Clostridium butyricum strains, and the absence of this gene in non-toxigenic C. butyricum strains. FEMS Microbiol. Lett. 99:251256.
55. Hauser, D.,, M. Gibert,, M. W. Eklund,, P. Boquet,, and M. R. Popoff. 1993. Comparative analysis of C3 and botulinal neurotoxin genes and their environment in Clostridium botulinum types C and D. J. Bacteriol. 175:72607268.
56. Hauser, D.,, M. Gibert,, J. C. Marvaud,, M. W. Eklund,, and M. R. Popoff. 1995. Botulinal neurotoxin C1 complex genes, clostridial neurotoxin homology and genetic transfer in Clostridium botulinum. Toxicon 33:515526.
57. Hendrix, R. W. 2003. Bacteriophage genomics. Curr. Opin. Microbiol. 6:506511.
58. Hendrix, R. W.,, M. C. M. Smith,, R. N. Burns,, M. E. Ford,, and G. F. Hatfull. 1999. Evolutionary relationships among diverse bacteriophages and prophages: all the world’s a phage. Proc. Natl. Acad. Sci. USA 96:21922197.
59. Holmes, R. K. 1976. Characterization and genetic mapping of nontoxinogenic (tox) mutants of corynebacteriophage beta. J. Virol. 19:195207.
60. Holmes, R. K. 2000. Biology and molecular epidemiology of diphtheria toxin and the tox gene. J. Infect. Dis. 181(Suppl. 1):S156S157.
61. Holmes, R. K.,, and L. Barksdale. 1969. Genetic analysis of tox+ and tox bacteriophages of Corynebacterium diphtheriae. J. Virol. 3:586598.
62. Hull, T. G. 1963. Diseases Transmitted from Animals to Man, 5th ed. Charles C Thomas, Springfield, Ill.
63. Hutson, R. A.,, Y. Zhou,, M. D. Collins,, E. A. Johnson,, C. L. Hatheway,, and H. Sugiyama. 1996. Genetic characterization of Clostridium botulinum type A containing silent type B neurotoxin gene sequences. J. Biol. Chem. 271:1078610792.
64. Inoue, K.,, and H. Iida. 1968. Bacteriophages of Clostridium botulinum. J. Virol. 2:537540.
65. Inoue, K.,, and H. Iida. 1970. Conversion of toxigenicity in Clostridium botulinum type C. Jpn. J. Microbiol. 14:8789.
66. Inoue, K.,, and H. Iida. 1971. Phage conversion of toxigenicity in Clostridium botulinum types C and D. Jpn. J. Med. Sci. 24:5356.
67. Johnson, E. A.,, J. H. Nelson,, and M. Johnson. 1990. Microbiological safety of cheese made from heat-treated milk. Part II. Microbiology. J. Food Prot. 53:519540.
68. Johnson, E. A.,, and M. C. Goodenough,. 1998. Botulism, p. 723741. In L. Collier,, A. Balows,, and M. Sussman (ed.), Topley and Wilson’s Microbiology and Microbial Infections, 9th ed., vol. 3. Arnold, London, United Kingdom.
69. Johnson, E. A. 1999. Clostridial toxins as therapeutic agents: benefits of nature’s most toxic proteins. Annu. Rev. Microbiol. 53:551575.
70. Johnson, E. A.,, w.-J. Lin,, Y.-T. Zhou,, and M. Bradshaw. 1997. Characterization of neurotoxin mutants in Clostridium botulinum type A. Clin. Infect. Dis. 25(Suppl. 2):S168S170.
71. Kaczorek, M.,, F. Delpeyroux,, N. Chenciner,, R. E. Streeck,, J. R. Murphy,, P. Boquet,, and P. Tiollais. 1983. Nucleotide sequence and expression of the diphtheria tox228 gene in Escherichia coli. Science 221:855858.
72. Kaplan, D. A.,, L. Naumovski,, and R. J. Collier. 1981. Chromogenic detection of antigen in bacteriophage plaques: a microplaque method applicable to large-scale screening. Gene 13:211220.
73. Kimura, K.,, N. Fujii,, K. Tsuzuki,, T. Murakami,, T. Indoh,, N. Yokosawa,, K. Takeshi,, B. Syuto,, and K. Oguma. 1990. The complete nucleotide sequence of the gene coding for botulinum type C1 toxin in the C-ST phage genome. Biochem. Biophys. Res. Commun. 171:13041311.
74. Kinouchi, t.,, K. Takumi,, and T. Kawata. 1981. Characterization of two inducible bacteriophages, α-1 and α-2, isolated from Clostridium botulinum type A 190L and their deoxyribonucleic acids. Microbiol. Immunol. 25:915927.
75. Krüger, D. H.,, and T. A. Bickle. 1983. Bacteriophage survival:multiple mechanisms for avoiding the deoxyribonucleic acid restriction systems of their hosts. Microbiol. Rev. 47:345360.
76. Laird, W.,, and N. Groman. 1976. Prophage map of converting corynebacteriophage beta. J. Virol. 19:208219.
77. Laird, W.,, and N. Groman. 1976. Orientation of the tox gene in the prophage of corynebacteriophage beta. J. Virol. 19:228231.
78. Leong, D.,, and J. R. Murphy. 1985. Characterization of the diphtheria tox transcript in Corynebacterium diphtheriae and Escherichia coli. J. Bacteriol. 163:11141119.
79. Levin, B. R.,, and C. T. Bergstrom. 2000. Bacteria are different: observations, interpretations, speculations, and opinions about the mechanisms of adaptive evolution in prokaryotes. Proc. Natl. Acad. Sci. USA 97:69816985.
80. Lin, W.-J.,, and E. A. Johnson. 1995. Genome analysis of Clostridium botulinum type A by pulsedfield gel electrophoresis. Appl. Environ. Microbiol. 61:44414447.
81. Lipsky, B. A.,, A. C. Goldberger,, L. S. Tomkins,, and J. J. Plorde. 1982. Infections caused by nondiphtheria corynebacteria. Rev. Infect. Dis. 4:12201235.
82. Love, J. F.,, and J. R. Murphy,. 2000. Corynebacterium diphtheriae: iron-mediated activation of DtxR and regulation of diphtheria toxin expression, p. 573582. In V. A. Fischetti,, R. P. Novick,, J. J. Ferretti,, D. A. Portnoy,, and J. I. Rood (ed.), Gram-Positive Pathogens. ASM Press, Washington, D. C.
83. Lwoff, A. 1953. Lysogeny. Bacteriol. Rev. 17:269337.
84. Matsuda, M.,, and L. Barksdale. 1966. Phagedirected synthesis of diphtherial toxin in nontoxigenic Corynebacterium diphtheriae. Nature 210:911913.
85. Matsuda, M.,, and L. Barksdale. 1967. System for the investigation of the bacteriophage-directed synthesis of diphtheria toxin. J. Bacteriol. 93:722730.
86. Miao, E. A.,, and S. I. Miller. 1999. Bacteriophages in the evolution of pathogen-host interactions. Proc. Natl. Acad. Sci. USA 96:94529454.
87. Minton, N. P., 1995. Molecular genetics of clostridial neurotoxins, p. 161194. In C. Montecucco (ed.), Clostridial Neurotoxins. Springer, Berlin, Germany.
88. Moriishi, K.,, M. Koura,, N. Abe,, N. Fujii,, Y. Fujinaga,, K. Inoue,, and K. Oguma. 1996. Mosaic structures of neurotoxins produced from Clostridium botulinum types C and D organisms. Biochim. Biophys. Acta 1307:123126.
89. Moriishi, K.,, M. Koura,, N. Fujii,, Y. Fujinaga,, K. Inoue,, B. Syuto,, and K. Oguma. 1996. Molecular cloning of the gene encoding the mosaic neurotoxin, composed of parts of botulinum neurotoxin types C1 and D, and PCR detection of the gene from Clostridium botulinum type C organisms. Appl. Environ. Microbiol. 62:662667.
90. Mueller, J. H. 1941. The influence of iron on the production of diphtheria toxin. J. Immunol. 42:343351.
91. Mueller, J. H.,, and P. A. Miller. 1941. Production of diphtheria toxin of high potency (100 Lf) on a reproducible medium. J. Immunol. 40:2132.
92. Murphy, J. R.,, A. M. Pappenheimer, Jr.,, and S. T. de Borms. 1974. Synthesis of diphtheria tox-gene products in Escherichia coli extracts. Proc. Natl. Acad. Sci. USA 71:1115.
93. Nako, H.,, J. M. Pruckler,, I. K. Mazurova,, O. V. Narvskaia,, T. Glushkevich,, V. F. Marijevski,, A. N. Kravetz,, B. S. Fields,, I. K. Wachsmuth,, and T. Popovic. 1996. Heterogeneity of the diphtheria toxin gene, tox, and its regulatory element dtxR, in Corynebacterium diphtheriae strains causing epidemic diphtheria in Russia and the Ukraine. J. Clin. Microbiol. 34:17111716.
94. Nieves, B. M.,, F. Gil,, and F. J. Castillo. 1981. Growth inhibition activity and bacteriophage and bacteriocin-like particles associated with different species of Clostridium. Can. J. Microbiol. 27:216225.
95. Novick, R. P. 2003. Mobile genetic elements and bacterial toxinoses: the superantigen-encoding pathogenicity islands of Staphylococcus aureus. Plasmid 49:93105.
96. Ogata, S.,, and M. Hongo. 1979. Bacteriophages of the genus Clostridium. Adv. Appl. Microbiol. 25:241273.
97. Oguma, K. 1976. The stability of toxigenicity in Clostridium botulinum type C. Jpn. J. Microbiol. 14:8789.
98. Oguma, K.,, Y. Fujinaga,, and E. Inoue. 1995. Structure and function of Clostridium botulinum toxins. Microbiol. Immunol. 39:161168.
99. Oguma, K.,, H. Iida,, and K. Inoue. 1975. Bacteriophages and toxigenicity in Clostridium botulinum types C and D. Jpn. J. Med. Sci. Biol. 28:6366.
100. Oguma, K.,, H. Iida,, and K. Inoue. 1975. Observations on nonconverting phage, c-n71, obtained from a nontoxigenic strain of Clostridium botulinum type C. Jpn. J. Microbiol. 19:167172.
101. Oguma, K.,, H. Iida,, and M. Shiozaki. 1976. Phage conversion to hemagglutinin production in Clostridium botulinum types C and D. Infect. Immun. 14:597602.
102. Oguma, K.,, H. Iida,, M. Shiozaki,, and I. Inoue. 1976. Antigenicity of converting phages obtained from Clostridium botulinum types C and D. Infect. Immun. 13:855860.
103. Pappenheimer, A. M., Jr. 1980. Diphtheria: studies on the biology of an infectious disease. Harvey Lect. 76:4573.
104. Pappenheimer, A. M., Jr. 1993. The story of a toxic protein, 1888-1992. Protein Sci. 2:292298.
105. Pappenheimer, A. M., Jr.,, and S. Johnson. 1936. Studies on diphtheria toxin production. I. The effect of iron and copper. Br. J. Exp. Pathol. 17:335341.
106. Popoff, M. R.,, D. Hauser,, P. Boquet,, M. W. Eklund,, and D. M. Gill. 1991. Characterization of the C3 gene of Clostridium botulinum types C and D and its expression in Escherichia coli. Infect. Immun. 59:36733679.
107. Popovic, T.,, I. K. Mazurova,, A. Efstratiou,, J. Vuopio-Varkila,, M. W. Reeves,, A. De Zoysa,, T. Glushkevich,, and P. Grimont. 2000. Molecular epidemiology of diphtheria. J. Infect. Dis. 181(Suppl. 1):S168S177.
108. Prescott, L. M.,, and R. A. Altenberg. 1967. Inducible lysis in Clostridium tetani. J. Bacteriol. 93:12201226.
109. Prescott, L. M.,, and R. A. Altenberg. 1976. Detection of bacteriophages from two strains of Clostridium tetani. J. Virol. 1:10851086.
110. Rappuoli, R.,, and G. Ratti. 1984. Physical map of the chromosomal region of Corynebacterium diphtheriae containing corynephage attachment sites attB1 and attB2. J. Bacteriol. 158:325330.
111. Ratti, G.,, A. Covacci,, and R. Rappuoli. 1997. A Trna2Arg gene of Corynebacterium diphtheriae is the chromosomal integration site for toxinogenic bacteriophages. Mol. Microbiol. 25:11791181.
112. Riegel, P.,, R. Ruimy,, D. de Briel,, G. Prevost,, F. Jehl,, R. Christen,, and H. Monteil. 1995. Taxonomy of Corynebacterium diphtheriae and related taxa, with recognition of Cornynebacterium ulcerans sp. nov. nom. rev. FEMS Microbiol. Lett. 126:271276.
113. Sakaguchi, G. 1983. Clostridium botulinum toxins. Pharmacol. Ther. 19:165194.
114. Schallehn, G.,, and M. W. Eklund. 1980. Conversion of Clostridium novyi type D (C. haemolyticum) to alpha toxin production by phages of C. novyi type A. FEMS Microbiol. Lett. 7:8386.
115. Schantz, E. J.,, and E. A. Johnson. 1992. Properties and use of botulinum toxin and other microbial toxins in medicine. Microbiol. Rev.56:8099.
116. Simpson, L. L. 2004. Identification of the major steps in botulinum toxin action. Annu. Rev. Pharmacol. Toxicol. 44:167193.
117. Sing, A.,, M. Hogardt,, S. Bierschenk,, and J. Heeseman. 2003. Detection of differences in the nucleotide and amino acid sequences of diphtheria toxin from Corynebacterium diphtheriae and Corynebacterium ulcerans causing extrapharyngeal infections. J. Clin. Microbiol. 41:48484851.
118. Singh, J.,, A.K. Harit,, D. C. Jain,, R. C. Panda,, K. N. Tewari,, R. Bhatia,, and J. Sokhey. 1999. Diphtheria is declining but continues to kill many children: analysis of data from a sentinel centre in Delhi, 1997. Epidemiol. Infect. 123:209215.
119. Songer, J. G. 1996. Clostridial diseases of domestic animals. Clin. Microbiol. Rev. 9:216234.
120. Sugiyama, H. 1980. Clostridium botulinum neurotoxin. Microbiol. Rev. 44:419448.
121. Sugiyama, H.,, and G. J. King. 1972. Isolation and taxonomic significance of bacteriophages for non-proteolytic Clostridium botulinum. J. Gen. Microbiol. 70:517525.
122. Sunagawa, H.,, and K. Inoue. 1991. Isolation and characterization of converting and non-converting phages, harbored in the strains of Clostridium botulinum types C and D isolated in Japan. J. Vet. Med. Sci. 53:951954.
123. Sunagawa, H.,, and K. Inoue. 1992. Biological and biophysical characteristics of phages isolated from Clostridium botulinum type C and D strains, and physicochemical properties of the phage DNAs. J. Vet. Med. Sci. 54:675684.
124. Sunagawa, H.,, T. Ohyama,, T. Watanabe,, and K. Inoue. 1992. The complete amino acid sequence of the Clostridium botulinum type D neurotoxin, deduced by nucleotide sequence analysis of the encoding phage d-16ϕ genome. J. Vet. Med. Sci. 54:905913.
125. Takumi, K.,, T. Kinouchi,, and T. Kawata. 1980. Isolation of two inducible bacteriophages from Clostridium botulinum type A 190L. FEMS Microbiol. Lett. 9:2327.
126. Tao, X.,, N. Schiering,, H. Y. Zeng,, D. Ringe,, and J. R. Murphy. 1994. Iron, DtxR, and the regulation of diphtheria toxin expression. Mol. Microbiol. 14:191197.
127. Taylor, D. E.,, and A. Guha. 1974. Asymmetric transcription during development of F1, a bacteriophage specific for Clostridium sporogenes. Virology 59:190200.
128. Taylor, D. E.,, and A. Guha. 1975. Development of bacteriophage F1 in Clostridium sporogenes: characterization of RNA transcripts. J. Virol. 16:107115.
129. Taylor, R. K. 1999. Virus on virus infects bacterium. Nature 399:312313.
130. Tharmaphornpilas, P.,, P. Yoocharoan,, P. Prempree,, S. Youngpairoj,, P. Sriprasert,, and C. R. Vitek. 2001. Diphtheria in Thailand in the 1990’s. J. Infect. Dis. 184:10351040.
131. Turner, S. L.,, M. J. Bailey,, A. K. Lilley,, and C. M. Thomas. 2002. Ecological and molecular maintenance strategies of mobile genetic elements. FEMS Microbiol. Ecol. 42:177185.
132. Uchida, T. 1983. Diphtheria toxin. Pharmacol. Ther. 19:107122.
133. Uchida, T.,, D. M. Gill,, and A. M. Pappenheimer, Jr. 1971. Mutation in the structural gene of diphtheria toxin carried by temperate phage. Nat. New Biol. 233:811.
134. Uchida, T.,, A. M. Pappenheimer, Jr.,, and A. A. Harper. 1973. Diphtheria toxin and related proteins. III. Reconstitution of hybrid “diphtheria toxin” from nontoxic mutant proteins. J. Biol. Chem. 248:38513854.
135. Uchida, T.,, A. M. Pappenheimer, Jr.,, and R. Greany. 1973. Diphtheria toxin and related proteins. I. Isolation and properties of mutant proteins serologically related to diphtheria toxin. J. Biol. Chem. 248:38383844.
136. van Helvoort, T. 1994. The construction of bacteriophage as bacterial virus: linking endogenous and exogenous thought styles. J. Hist. Biol. 27:91139.
137. vanHeyningen, W. E. 1950. Bacterial Toxins. Blackwell Publications, Oxford, United Kingdom.
138. Vitek, C. R.,, and E. Y. Bogatyreva. 2000. Diphtheria surveillance and control in the former Soviet Union and the newly independent states. J. Infect. Dis. 181(Suppl. 1):S23S26.
139. White, A.,, X. Ding,, J. C. Vanderspek,, J. R. Murphy,, and D. Ringe. 1998. Structure of the metal-ion-activated diphtheria toxin repressor/tox operator complex. Nature 394:502506.
140. Wood, W. B., Jr.,, and B. R. Davis,. 1980. Hostparasite relations in bacterial infections, p. 552571. In B. R. Davis,, R. Dulbecco,, H. N. Eisen,, and H. S. Ginsberg (ed.), Microbiology, 3rd ed. Harper and Row, Philadelphia, Pa.
141. Yamaizumi, M.,, E. Mekada,, T. Uchida,, and Y. Okada. 1978. One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell 15:245250.
142. Zhou, Y.,, H. Sugiyama,, and E. A. Johnson. 1993. Transfer of neurotoxigenicity from Clostridium butyricum to a nontoxigenic Clostridium botulinum type E-like strain. Appl. Environ. Microbiol. 59:38253831.
143. Zhou, Y.,, H. Sugiyama,, H. Nakano,, and E. A. Johnson. 1995. The genes for the Clostridium botulinum type G toxin complex are on a plasmid. Infect. Immun. 63:20872091.
144. Zimmer, M.,, S. Scherer,, and M. Loessner. 2002. Genomic analysis of Clostridium perfringens bacteriophage ϕ3626, which integrates into guaA and possibly affects sporulation. J. Bacteriol. 184:43594368.


Generic image for table

Properties of neurotoxigenic clostridia

Adapted from references and with permission of the publishers.

Citation: Johnson E. 2005. Bacteriophages Encoding Botulinum and Diphtheria Toxins, p 280-296. In Waldor M, Friedman D, Adhya S (ed), Phages. ASM Press, Washington, DC. doi: 10.1128/9781555816506.ch14

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error