Botulinum neurotoxin diversity from a gene-centered view

Toxins

Volumn 10, Issue 8, 2018, Pages

  Benoit, Roger M ^a  

^a PAUL SCHERRER INSTITUTE   (Switzerland)

Author keywords

Botulinum neurotoxin evolution; Carcass; Gene centered view; Maggot cycle; Selfish genes; The role of botulinum neurotoxins in nature; Toxin architecture; Toxin diversity

Indexed keywords

BOTULINUM TOXIN; NEUROTOXIN; BACTERIAL DNA;

ANAEROBIC BACTERIUM; ARTICLE; BACTERIAL GROWTH; BACTERIAL SPORE; BLOOD BRAIN BARRIER; BLOODSTREAM INFECTION; BOTULISM; CARCASS; CLOSTRIDIA; CLOSTRIDIUM BOTULINUM; NERVE CELL; NEUROTRANSMITTER RELEASE; NONHUMAN; ANIMAL; EVOLUTION; GENETICS; HUMAN;

ANIMALS; BIOLOGICAL EVOLUTION; BOTULINUM TOXINS; BOTULISM; CLOSTRIDIUM BOTULINUM; DNA, BACTERIAL; HUMANS; NEUROTOXINS;

EID: 85051282948     PISSN: None     EISSN: 20726651     Source Type: Journal    
DOI: 10.3390/toxins10080310     Document Type: Article

References (96)

1. Hill, K.K.; Smith, T.J. Genetic diversity within Clostridium botulinum serotypes, botulinum neurotoxin gene clusters and toxin subtypes. Curr. Top. Microbiol. Immunol. 2013, 364, 1–20. [PubMed]
2. Peck, M.W. Biology and genomic analysis of Clostridium botulinum. Adv. Microb. Physiol. 2009, 55, 183–265, 320. [PubMed]
3. Shukla, H.D.; Sharma, S.K. Clostridium botulinum: A bug with beauty and weapon. Crit. Rev. Microbiol. 2005, 31, 11–18. [CrossRef] [PubMed]
4. Arnon, S.S.; Schechter, R.; Inglesby, T.V.; Henderson, D.A.; Bartlett, J.G.; Ascher, M.S.; Eitzen, E.; Fine, A.D.; Hauer, J.; Layton, M.; et al. Botulinum toxin as a biological weapon: Medical and public health management. JAMA 2001, 285, 1059–1070. [CrossRef] [PubMed]
5. Johnson, E.A.; Montecucco, C. Botulism. Handb. Clin. Neurol. 2008, 91, 333–368. [PubMed]
6. Carruthers, J.; Carruthers, A. Botox: Beyond wrinkles. Clin. Dermatol. 2004, 22, 89–93. [CrossRef] [PubMed]
7. Markey, A.C. Botulinum A exotoxin in cosmetic dermatology. Clin. Exp. Dermatol. 2000, 25, 173–175. [CrossRef] [PubMed]
8. Erbguth, F.J. Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin. Mov. Disord. 2004, 19 (Suppl. 8), S2–S6. [CrossRef] [PubMed]
9. Hill, K.K.; Xie, G.; Foley, B.T.; Smith, T.J.; Munk, A.C.; Bruce, D.; Smith, L.A.; Brettin, T.S.; Detter, J.C. Recombination and insertion events involving the botulinum neurotoxin complex genes in Clostridium botulinum types A, B, E and F and Clostridium butyricum type E strains. BMC Biol. 2009, 7, 66. [CrossRef] [PubMed]
10. Montecucco, C.; Rasotto, M.B. On botulinum neurotoxin variability. MBio 2015, 6, e02131-14. [CrossRef] [PubMed]
11. Arndt, J.W.; Jacobson, M.J.; Abola, E.E.; Forsyth, C.M.; Tepp, W.H.; Marks, J.D.; Johnson, E.A.; Stevens, R.C. A structural perspective of the sequence variability within botulinum neurotoxin subtypes A1–A4. J. Mol. Biol. 2006, 362, 733–742. [CrossRef] [PubMed]
12. Hill, K.K.; Smith, T.J.; Helma, C.H.; Ticknor, L.O.; Foley, B.T.; Svensson, R.T.; Brown, J.L.; Johnson, E.A.; Smith, L.A.; Okinaka, R.T.; et al. Genetic diversity among Botulinum Neurotoxin-producing clostridial strains. J. Bacteriol. 2007, 189, 818–832. [CrossRef] [PubMed]
13. Lacy, D.B.; Stevens, R.C. Sequence homology and structural analysis of the clostridial neurotoxins. J. Mol. Biol. 1999, 291, 1091–1104. [CrossRef] [PubMed]
14. Dineen, S.S.; Bradshaw, M.; Johnson, E.A. Neurotoxin gene clusters in Clostridium botulinum type A strains: Sequence comparison and evolutionary implications. Curr. Microbiol. 2003, 46, 345–352. [CrossRef] [PubMed]
15. Peck, M.W.; Smith, T.J.; Anniballi, F.; Austin, J.W.; Bano, L.; Bradshaw, M.; Cuervo, P.; Cheng, L.W.; Derman, Y.; Dorner, B.G.; et al. Historical Perspectives and Guidelines for Botulinum Neurotoxin Subtype Nomenclature. Toxins 2017, 9, 38. [CrossRef] [PubMed]
16. Rossetto, O.; Pirazzini, M.; Montecucco, C. Botulinum neurotoxins: Genetic, structural and mechanistic insights. Nat. Rev. Microbiol. 2014, 12, 535–549. [CrossRef] [PubMed]
17. Montal, M. Botulinum neurotoxin: A marvel of protein design. Annu. Rev. Biochem. 2010, 79, 591–617. [CrossRef] [PubMed]
18. Chatla, K.; Gaunt, P.S.; Petrie-Hanson, L.; Ford, L.; Hanson, L.A. Zebrafish Sensitivity to Botulinum Neurotoxins. Toxins 2016, 8, 132. [CrossRef] [PubMed]
19. Torii, Y.; Goto, Y.; Nakahira, S.; Kozaki, S.; Kaji, R.; Ginnaga, A. Comparison of Systemic Toxicity between Botulinum Toxin Subtypes A1 and A2 in Mice and Rats. Basic Clin. Pharmacol. Toxicol. 2015, 116, 524–528. [CrossRef] [PubMed]
20. Kohda, T.; Nakamura, K.; Hosomi, K.; Torii, Y.; Kozaki, S.; Mukamoto, M. Characterization of the functional activity of botulinum neurotoxin subtype B6. Microbiol. Immunol. 2017, 61, 482–489. [CrossRef] [PubMed]
21. Skarin, H.; Lindgren, Y.; Jansson, D.S. Investigations into an Outbreak of Botulism Caused by Clostridium botulinum Type C/D in Laying Hens. Avian Dis. 2015, 59, 335–340. [CrossRef] [PubMed]
22. Hanson-Smith, V.; Johnson, A. PhyloBot: A Web Portal for Automated Phylogenetics, Ancestral Sequence Reconstruction, and Exploration of Mutational Trajectories. PLoS Comput. Biol. 2016, 12, e1004976. [CrossRef] [PubMed]
23. Popoff, M.R. Ecology of neurotoxigenic strains of clostridia. In Clostridial Neurotoxins—The Molecular Pathogenesis of Tetanus and Botulism; Montecucco, C., Ed.; Springer: Berlin, Germany, 1995; pp. 1–29.
24. Deurenberg, R.H.; Bathoorn, E.; Chlebowicz, M.A.; Couto, N.; Ferdous, M.; Garcia-Cobos, S.; Kooistra-Smid, A.M.; Raangs, E.C.; Rosema, S.; Veloo, A.C.; et al. Application of next generation sequencing in clinical microbiology and infection prevention. J. Biotechnol. 2017, 243, 16–24. [CrossRef] [PubMed]
25. Doxey, A.C.; Mansfield, M.J.; Montecucco, C. Discovery of novel bacterial toxins by genomics and computational biology. Toxicon 2018, 147, 2–12. [CrossRef] [PubMed]
26. Gu, S.; Jin, R. Assembly and function of the botulinum neurotoxin progenitor complex. Curr. Top. Microbiol. Immunol. 2013, 364, 21–44. [PubMed]
27. Amatsu, S.; Sugawara, Y.; Matsumura, T.; Kitadokoro, K.; Fujinaga, Y. Crystal structure of Clostridium botulinum whole hemagglutinin reveals a huge triskelion-shaped molecular complex. J. Biol. Chem. 2013, 288, 35617–35625. [CrossRef] [PubMed]
28. Arndt, J.W.; Gu, J.; Jaroszewski, L.; Schwarzenbacher, R.; Hanson, M.A.; Lebeda, F.J.; Stevens, R.C. The structure of the neurotoxin-associated protein HA33/A from Clostridium botulinum suggests a reoccurring beta-trefoil fold in the progenitor toxin complex. J. Mol. Biol. 2005, 346, 1083–1093. [CrossRef] [PubMed]
29. Hasegawa, K.; Watanabe, T.; Suzuki, T.; Yamano, A.; Oikawa, T.; Sato, Y.; Kouguchi, H.; Yoneyama, T.; Niwa, K.; Ikeda, T.; et al. A novel subunit structure of Clostridium botulinum serotype D toxin complex with three extended arms. J. Biol. Chem. 2007, 282, 24777–24783. [CrossRef] [PubMed]
30. Inoue, K.; Sobhany, M.; Transue, T.R.; Oguma, K.; Pedersen, L.C.; Negishi, M. Structural analysis by X-ray crystallography and calorimetry of a haemagglutinin component (HA1) of the progenitor toxin from Clostridium botulinum. Microbiology 2003, 149, 3361–3370. [CrossRef] [PubMed]
31. Lee, K.; Gu, S.; Jin, L.; Le, T.T.; Cheng, L.W.; Strotmeier, J.; Kruel, A.M.; Yao, G.; Perry, K.; Rummel, A.; et al. Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity. PLoS Pathog. 2013, 9, e1003690. [CrossRef] [PubMed]
32. Lee, K.; Lam, K.H.; Kruel, A.M.; Perry, K.; Rummel, A.; Jin, R. High-resolution crystal structure of HA33 of botulinum neurotoxin type B progenitor toxin complex. Biochem. Biophys. Res. Commun. 2014, 446, 568–573. [CrossRef] [PubMed]
33. Nakamura, T.; Kotani, M.; Tonozuka, T.; Ide, A.; Oguma, K.; Nishikawa, A. Crystal structure of the HA3 subcomponent of Clostridium botulinum type C progenitor toxin. J. Mol. Biol. 2009, 385, 1193–1206. [CrossRef] [PubMed]
34. Nakamura, T.; Tonozuka, T.; Ito, S.; Takeda, Y.; Sato, R.; Matsuo, I.; Ito, Y.; Oguma, K.; Nishikawa, A. Molecular diversity of the two sugar-binding sites of the beta-trefoil lectin HA33/C (HA1) from Clostridium botulinum type C neurotoxin. Arch. Biochem. Biophys. 2011, 512, 69–77. [CrossRef] [PubMed]
35. Yamashita, S.; Yoshida, H.; Uchiyama, N.; Nakakita, Y.; Nakakita, S.; Tonozuka, T.; Oguma, K.; Nishikawa, A.; Kamitori, S. Carbohydrate recognition mechanism of HA70 from Clostridium botulinum deduced from X-ray structures in complexes with sialylated oligosaccharides. FEBS Lett. 2012, 586, 2404–2410. [CrossRef] [PubMed]
36. Lee, K.; Zhong, X.; Gu, S.; Kruel, A.M.; Dorner, M.B.; Perry, K.; Rummel, A.; Dong, M.; Jin, R. Molecular basis for disruption of E-cadherin adhesion by botulinum neurotoxin A complex. Science 2014, 344, 1405–1410. [CrossRef] [PubMed]
37. Brunt, J.; Carter, A.T.; Stringer, S.C.; Peck, M.W. Identification of a novel botulinum neurotoxin gene cluster in Enterococcus. FEBS Lett. 2018, 592, 310–317. [CrossRef] [PubMed]
38. Gustafsson, R.; Berntsson, R.P.; Martinez-Carranza, M.; El, T.G.; Odegrip, R.; Johnson, E.A.; Stenmark, P. Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster. FEBS Lett. 2017, 591, 3781–3792. [CrossRef] [PubMed]
39. Lam, K.H.; Qi, R.; Liu, S.; Kroh, A.; Yao, G.; Perry, K.; Rummel, A.; Jin, R. The hypothetical protein P47 of Clostridium botulinum E1 strain Beluga has a structural topology similar to bactericidal/permeability-increasing protein. Toxicon 2018, 147, 19–26. [CrossRef] [PubMed]
40. Hill, K.K.; Xie, G.; Foley, B.T.; Smith, T.J. Genetic diversity within the botulinum neurotoxin-producing bacteria and their neurotoxins. Toxicon 2015, 107, 2–8. [CrossRef] [PubMed]
41. East, A.K.; Bhandari, M.; Stacey, J.M.; Campbell, K.D.; Collins, M.D. Organization and phylogenetic interrelationships of genes encoding components of the botulinum toxin complex in proteolytic Clostridium botulinum types A, B, and F: Evidence of chimeric sequences in the gene encoding the nontoxic nonhemagglutinin component. Int. J. Syst. Bacteriol. 1996, 46, 1105–1112. [CrossRef] [PubMed]
42. Smith, T.J.; Hill, K.K.; Xie, G.; Foley, B.T.; Williamson, C.H.D.; Foster, J.T.; Johnson, S.L.; Chertkov, O.; Teshima, H.; Gibbons, H.S.; et al. Genomic sequences of six botulinum neurotoxin-producing strains representing three clostridial species illustrate the mobility and diversity of botulinum neurotoxin genes. Infect. Genet. Evol. 2015, 30, 102–113. [CrossRef] [PubMed]
43. Espelund, M.; Klaveness, D. Botulism outbreaks in natural environments—An update. Front. Microbiol. 2014, 5, 287. [CrossRef] [PubMed]
44. Goodsell, D.S. Our Molecular Nature—The Body’s Motors, Machines and Messages; Springer: New York, NY, USA, 1996.
45. Singh, B.R. Intimate details of the most poisonous poison. Nat. Struct. Biol. 2000, 7, 617–619. [CrossRef] [PubMed]
46. Colasante, C.; Rossetto, O.; Morbiato, L.; Pirazzini, M.; Molgo, J.; Montecucco, C. Botulinum neurotoxin type A is internalized and translocated from small synaptic vesicles at the neuromuscular junction. Mol. Neurobiol. 2013, 48, 120–127. [CrossRef] [PubMed]
47. Wenham, T.N. Botulism: A rare complication of injecting drug use. Emerg. Med. J. 2008, 25, 55–56. [CrossRef] [PubMed]
48. Sobel, J. Botulism. Clin. Infect. Dis. 2005, 41, 1167–1173. [CrossRef] [PubMed]
49. Sobel, J.; Tucker, N.; Sulka, A.; McLaughlin, J.; Maslanka, S. Foodborne botulism in the United States, 1990–2000. Emerg. Infect. Dis. 2004, 10, 1606–1611. [CrossRef] [PubMed]
50. Grabowski, N.T.; Klein, G. Microbiology and foodborne pathogens in honey. Crit. Rev. Food Sci. Nutr. 2017, 57, 1852–1862. [PubMed]
51. Dong, M.; Yeh, F.; Tepp, W.H.; Dean, C.; Johnson, E.A.; Janz, R.; Chapman, E.R. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006, 312, 592–596. [CrossRef] [PubMed]
52. Benoit, R.M.; Frey, D.; Hilbert, M.; Kevenaar, J.T.; Wieser, M.M.; Stirnimann, C.U.; McMillan, D.; Ceska, T.; Lebon, F.; Jaussi, R.; et al. Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A. Nature 2014, 505, 108–111. [CrossRef] [PubMed]
53. Mahrhold, S.; Rummel, A.; Bigalke, H.; Davletov, B.; Binz, T. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. FEBS Lett. 2006, 580, 2011–2014. [CrossRef] [PubMed]
54. Rummel, A.; Karnath, T.; Henke, T.; Bigalke, H.; Binz, T. Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G. J. Biol. Chem. 2004, 279, 30865–30870. [CrossRef] [PubMed]
55. Nishiki, T.; Tokuyama, Y.; Kamata, Y.; Nemoto, Y.; Yoshida, A.; Sekiguchi, M.; Takahashi, M.; Kozaki, S. Binding of botulinum type B neurotoxin to Chinese hamster ovary cells transfected with rat synaptotagmin II cDNA. Neurosci. Lett. 1996, 208, 105–108. [CrossRef]
56. Dong, M.; Liu, H.; Tepp, W.H.; Johnson, E.A.; Janz, R.; Chapman, E.R. Glycosylated SV2A and SV2B mediate the entry of botulinum neurotoxin E into neurons. Mol. Biol. Cell 2008, 19, 5226–5237. [CrossRef] [PubMed]
57. Fu, Z.; Chen, C.; Barbieri, J.T.; Kim, J.J.; Baldwin, M.R. Glycosylated SV2 and gangliosides as dual receptors for botulinum neurotoxin serotype F. Biochemistry 2009, 48, 5631–5641. [CrossRef] [PubMed]
58. Dong, M.; Richards, D.A.; Goodnough, M.C.; Tepp, W.H.; Johnson, E.A.; Chapman, E.R. Synaptotagmins I and II mediate entry of botulinum neurotoxin B into cells. J. Cell Biol. 2003, 162, 1293–1303. [CrossRef] [PubMed]
59. Nishiki, T.; Kamata, Y.; Nemoto, Y.; Omori, A.; Ito, T.; Takahashi, M.; Kozaki, S. Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J. Biol. Chem. 1994, 269, 10498–10503. [PubMed]
60. Nishiki, T.; Tokuyama, Y.; Kamata, Y.; Nemoto, Y.; Yoshida, A.; Sato, K.; Sekiguchi, M.; Takahashi, M.; Kozaki, S. The high-affinity binding of Clostridium botulinum type B neurotoxin to synaptotagmin II associated with gangliosides GT1b/GD1a. FEBS Lett. 1996, 378, 253–257. [CrossRef]
61. Chai, Q.; Arndt, J.W.; Dong, M.; Tepp, W.H.; Johnson, E.A.; Chapman, E.R.; Stevens, R.C. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 2006, 444, 1096–1100. [CrossRef] [PubMed]
62. Simpson, L.L. Identification of the major steps in botulinum toxin action. Annu. Rev. Pharmacol. Toxicol. 2004, 44, 167–193. [CrossRef] [PubMed]
63. Lawrence, G.; Wang, J.; Chion, C.K.; Aoki, K.R.; Dolly, J.O. Two protein trafficking processes at motor nerve endings unveiled by botulinum neurotoxin E. J. Pharmacol. Exp. Ther. 2007, 320, 410–418. [CrossRef] [PubMed]
64. Simpson, L.L. Ammonium chloride and methylamine hydrochloride antagonize clostridial neurotoxins. J. Pharmacol. Exp. Ther. 1983, 225, 546–552. [PubMed]
65. Montecucco, C.; Schiavo, G.; DasGupta, B.R. Effect of pH on the interaction of botulinum neurotoxins A, B and E with liposomes. Biochem. J. 1989, 259, 47–53. [CrossRef] [PubMed]
66. Rossetto, O.; Montecucco, C. Presynaptic neurotoxins with enzymatic activities. Handb. Exp. Pharmacol. 2008, 129–170.
67. Rummel, A. The long journey of botulinum neurotoxins into the synapse. Toxicon 2015, 107, 9–24. [CrossRef] [PubMed]
68. Restani, L.; Giribaldi, F.; Manich, M.; Bercsenyi, K.; Menendez, G.; Rossetto, O.; Caleo, M.; Schiavo, G. Botulinum neurotoxins A and E undergo retrograde axonal transport in primary motor neurons. PLoS Pathog. 2012, 8, e1003087. [CrossRef] [PubMed]
69. Koriazova, L.K.; Montal, M. Translocation of botulinum neurotoxin light chain protease through the heavy chain channel. Nat. Struct. Biol. 2003, 10, 13–18. [CrossRef] [PubMed]
70. Lebrun, I.; Marques-Porto, R.; Pereira, A.S.; Pereira, A.; Perpetuo, E.A. Bacterial toxins: An overview on bacterial proteases and their action as virulence factors. Mini Rev. Med. Chem. 2009, 9, 820–828. [CrossRef] [PubMed]
71. Wobeser, G. Avian botulism—Another perspective. J. Wildl. Dis. 1997, 33, 181–186. [CrossRef] [PubMed]
72. Darwin, C. On the Origin of Species by Means of Natural Selection; John Murray: London, UK, 1859.
73. Dawkins, R. The Selfish Gene; Oxford University Press: London, UK, 1976.
74. Orgel, L.E.; Crick, F.H. Selfish DNA: The ultimate parasite. Nature 1980, 284, 604–607. [CrossRef] [PubMed]
75. Koonin, E.V.; Wolf, Y.I. The fundamental units, processes and patterns of evolution, and the tree of life conundrum. Biol. Direct 2009, 4, 33. [CrossRef] [PubMed]
76. Doolittle, W.F.; Sapienza, C. Selfish genes, the phenotype paradigm and genome evolution. Nature 1980, 284, 601–603. [CrossRef] [PubMed]
77. Dawkins, R. The Selfish Gene—40th Anniversary Edition—Oxford Landmark Science; Oxford University Press: London, UK, 2016.
78. Lawrence, J. Selfish operons: The evolutionary impact of gene clustering in prokaryotes and eukaryotes. Curr. Opin. Genet. Dev. 1999, 9, 642–648. [CrossRef]
79. Koonin, E.V.; Wolf, Y.I. Constraints and plasticity in genome and molecular-phenome evolution. Nat. Rev. Genet. 2010, 11, 487–498. [CrossRef] [PubMed]
80. Jalasvuori, M.; Koonin, E.V. Classification of prokaryotic genetic replicators: Between selfishness and altruism. Ann. N. Y. Acad. Sci. 2015, 1341, 96–105. [CrossRef] [PubMed]
81. Ben-David, E.; Burga, A.; Kruglyak, L. A maternal-effect selfish genetic element in Caenorhabditis elegans. Science 2017, 356, 1051–1055. [CrossRef] [PubMed]
82. Phadnis, N. Poisons, antidotes, and selfish genes. Science 2017, 356, 1013. [CrossRef] [PubMed]
83. Nuckolls, N.L.; Bravo Nunez, M.A.; Eickbush, M.T.; Young, J.M.; Lange, J.J.; Yu, J.S.; Smith, G.R.; Jaspersen, S.L.; Malik, H.S.; Zanders, S.E. wtf genes are prolific dual poison-antidote meiotic drivers. Elife 2017, 6, e26033. [CrossRef] [PubMed]
84. Van Melderen, L.; De Bast, M.S. Bacterial toxin-antitoxin systems: More than selfish entities? PLoS Genet. 2009, 5, e1000437.
85. Zhang, S.; Lebreton, F.; Mansfield, M.J.; Miyashita, S.I.; Zhang, J.; Schwartzman, J.A.; Tao, L.; Masuyer, G.; Martinez-Carranza, M.; Stenmark, P.; et al. Identification of a Botulinum Neurotoxin-like Toxin in a Commensal Strain of Enterococcus faecium. Cell Host Microbe 2018, 23, 169–176. [CrossRef] [PubMed]
86. Mansfield, M.J.; Adams, J.B.; Doxey, A.C. Botulinum neurotoxin homologs in non-Clostridium species. FEBS Lett. 2015, 589, 342–348. [CrossRef] [PubMed]
87. Zornetta, I.; Azarnia, T.D.; Arrigoni, G.; Anniballi, F.; Bano, L.; Leka, O.; Zanotti, G.; Binz, T.; Montecucco, C. The first non Clostridial botulinum-like toxin cleaves VAMP within the juxtamembrane domain. Sci. Rep. 2016, 6, 30257. [CrossRef] [PubMed]
88. Kelly, B.G.; Vespermann, A.; Bolton, D.J. The role of horizontal gene transfer in the evolution of selected foodborne bacterial pathogens. Food Chem. Toxicol. 2009, 47, 951–968. [CrossRef] [PubMed]
89. Skarin, H.; Segerman, B. Horizontal gene transfer of toxin genes in Clostridium botulinum: Involvement of mobile elements and plasmids. Mob. Genet. Elem. 2011, 1, 213–215. [CrossRef] [PubMed]
90. DasGupta, B.R. Botulinum neurotoxins: Perspective on their existence and as polyproteins harboring viral proteases. J. Gen. Appl. Microbiol. 2006, 52, 1–8. [CrossRef] [PubMed]
91. Roossinck, M.J.; Bazan, E.R. Symbiosis: Viruses as Intimate Partners. Annu. Rev. Virol. 2017, 4, 123–139. [CrossRef] [PubMed]
92. Mansfield, M.J.; Doxey, A.C. Genomic insights into the evolution and ecology of botulinum neurotoxins. Pathog. Dis. 2018, 76, fty040. [CrossRef] [PubMed]
93. Smith, T.J. Clostridium botulinum genomes and genetic diversity. In Molecular Aspects of Botulinum Neurotoxin, Current Topics in Neurotoxicity; Foster, K.A., Ed.; Springer: New York, NY, USA, 2014; pp. 207–228.
94. Anza, I.; Vidal, D.; Feliu, J.; Crespo, E.; Mateo, R. Differences in the Vulnerability of Waterbird Species to Botulism Outbreaks in Mediterranean Wetlands: An Assessment of Ecological and Physiological Factors. Appl. Environ. Microbiol. 2016, 82, 3092–3099. [CrossRef] [PubMed]
95. Bruggemann, H.; Brzuszkiewicz, E.; Chapeton-Montes, D.; Plourde, L.; Speck, D.; Popoff, M.R. Genomics of Clostridium tetani. Res. Microbiol. 2015, 166, 326–331. [CrossRef] [PubMed]
96. Kumar, R.; Chang, T.W.; Singh, B.R. Evolutionary trains of toxins. In Biological Toxins and Bioterrorism; Gopalakrishnakone, P., Balali-Mood, M., Llewellyn, L., Singh, B.R., Eds.; Springer: New York, NY, USA, 2015.