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Virulence Plasmids of the Pathogenic Clostridia

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  • Authors: Sarah A. Revitt-Mills1, Callum J. Vidor2, Thomas D. Watts3, Dena Lyras4, Julian I. Rood5, Vicki Adams6
  • Editors: Vincent A. Fischetti7, Richard P. Novick8, Joseph J. Ferretti9, Daniel A. Portnoy10, Miriam Braunstein11, Julian I. Rood12
    Affiliations: 1: Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia; 2: Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia; 3: Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia; 4: Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia; 5: Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia; 6: Infection and Immunity Program, Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia; 7: The Rockefeller University, New York, NY; 8: Skirball Institute for Molecular Medicine, NYU Medical Center, New York, NY; 9: Department of Microbiology & Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK; 10: Department of Molecular and Cellular Microbiology, University of California, Berkeley, Berkeley, CA; 11: Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC; 12: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
  • Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018
  • Received 29 May 2018 Accepted 16 August 2018 Published 17 May 2019
  • Vickie Adams, [email protected]
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  • Abstract:

    The clostridia cause a spectrum of diseases in humans and animals ranging from life-threatening tetanus and botulism, uterine infections, histotoxic infections and enteric diseases, including antibiotic-associated diarrhea, and food poisoning. The symptoms of all these diseases are the result of potent protein toxins produced by these organisms. These toxins are diverse, ranging from a multitude of pore-forming toxins to phospholipases, metalloproteases, ADP-ribosyltransferases and large glycosyltransferases. The location of the toxin genes is the unifying theme of this review because with one or two exceptions they are all located on plasmids or on bacteriophage that replicate using a plasmid-like intermediate. Some of these plasmids are distantly related whilst others share little or no similarity. Many of these toxin plasmids have been shown to be conjugative. The mobile nature of these toxin genes gives a ready explanation of how clostridial toxin genes have been so widely disseminated both within the clostridial genera as well as in the wider bacterial community.

  • Citation: Revitt-Mills S, Vidor C, Watts T, Lyras D, Rood J, Adams V. 2019. Virulence Plasmids of the Pathogenic Clostridia. Microbiol Spectrum 7(3):GPP3-0034-2018. doi:10.1128/microbiolspec.GPP3-0034-2018.


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The clostridia cause a spectrum of diseases in humans and animals ranging from life-threatening tetanus and botulism, uterine infections, histotoxic infections and enteric diseases, including antibiotic-associated diarrhea, and food poisoning. The symptoms of all these diseases are the result of potent protein toxins produced by these organisms. These toxins are diverse, ranging from a multitude of pore-forming toxins to phospholipases, metalloproteases, ADP-ribosyltransferases and large glycosyltransferases. The location of the toxin genes is the unifying theme of this review because with one or two exceptions they are all located on plasmids or on bacteriophage that replicate using a plasmid-like intermediate. Some of these plasmids are distantly related whilst others share little or no similarity. Many of these toxin plasmids have been shown to be conjugative. The mobile nature of these toxin genes gives a ready explanation of how clostridial toxin genes have been so widely disseminated both within the clostridial genera as well as in the wider bacterial community.

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Image of FIGURE 1

The pCS1 family plasmids of . Shown is a visual representation of a blastn analysis comparing each of the seven sequenced pCS1 plasmids to the reference sequence of pCS1-3 from strain JGS6382. The third ring from the center (green) and the coordinates (in kb) correspond to pCS1-3. Plasmids displaying 70 to 100% identity to pCS1-3 at a particular locus are shown with a solid block of colour on their respective ring. Identity to pCS1-3 between 50 and 70% is represented as a pale block of colour and if the identity is lower than 50% it is represented as a gap in the corresponding ring. Conserved loci on pCS1-3 are indicated as a gray arc on the outermost ring and labeled. Genes of interest are annotated as black arrows on the outermost ring and also labeled. Sequences analyzed and accession numbers: pCS1-1 (LN679999), pCS1-2 (LN681232), pCS1-3 (LN681235), pCS1-4 (LN681233), pCS1-5 (MG205643), pCS1-6 (MG205642), pCS1-7 (MG205641). Produced using BRIG ( 224 ).

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018
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Image of FIGURE 2

Nucleotide alignment of pCW3-like plasmids from . Full plasmid sequences were aligned using the blastn algorithm ( 225 ) and Easyfig for visualization ( 226 ). The plasmid names are noted on the left along with the toxin or antibiotic resistance determinants encoded within each plasmid sequence. Predicted (ORFs) are indicated by arrows with the following color code: conserved ORFs (light blue), conjugation genes, dark blue; toxin genes, yellow; partitioning genes, green; red; group II introns, pink; antibiotic resistance genes (orange) less-conserved ORFs, gray. The scale bar and key for nucleotide identity are shown.

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018
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Image of FIGURE 3

Model of the pCW3 conjugation apparatus. The arrangement of the proteins within the model is based on protein localization studies and bioinformatics analysis. Black arrows indicate confirmed protein interactions between Tcp proteins and only Tcp proteins required for wild-type transfer of pCW3 are shown. Indicated within the membrane are the integral membrane proteins TcpH (brown), the peptidoglycan hydrolase TcpG (purple), the assembly factor TcpC (green; monomers as different shades), the proteins of unknown function, TcpD (yellow) and TcpE (pink) and the putative coupling protein TcpA (orange). Within the cytoplasm are a putative ATPase TcpF (red) and the novel relaxase TcpM (blue) in complex with the double stranded pCW3 site. Dotted arrows indicate putative ATPase activity. Reproduced with permission from Wisniewski and Rood (2017).

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018
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Image of FIGURE 4

Sequence alignment of pCP13-like plasmids from . The plasmid sequences of pCP-TS1, pCP-OS1, pCP13 and pBCNF5603 were aligned using the Blastn algorithm using Easyfig ( 226 ). The percentage identity is indicated by the scale bar at the bottom right and each sequence is compared separately to the sequences above and below. ORFs are indicated by arrows and ORFs of particular interest are colored as follows: green, restriction modification systems; red, replication and maintenance; purple, toxin genes; yellow, transposase genes; dark blue, putative collagen adhesins; orange, putative relaxase enzymes.

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018
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Image of FIGURE 5

Blast analysis of the tetanus toxin plasmid family. Plasmid sequences derived from were compared to the 74 kb pE88 plasmid (GenBank accession number NC 004565). The two outermost rings show predicted (ORFs) for both the (+) and (-) DNA strands. The position of the tetanus toxin gene () and the regulator () are shown. DNA regions with less than 80% sequence identity are indicated by gaps. Strain ATCC 454 does not encode either the or genes. The regions denoted A through E indicate deletions within plasmids found in wildtype strains and include and DNA directed RNA polymerase sigma-70 factor (A), and an ABC anti-microbial transporter system (B), an / two-component system (C), and an ABC-type lipoprotein export system/permease complex (D), and another ABC multidrug-resistance transporter/permease complex (E). Reproduced with permission from Cohen (2017).

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018
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Image of FIGURE 6

Gene arrangement for toxin loci. The two basic loci types, + and +, are indicated. Similar genes are designated with the same color and the toxin gene serotype designation is given on the right.

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018
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The toxinotype classification scheme

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018
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Summary of BoNT-producing species and toxin gene locations

Source: microbiolspec May 2019 vol. 7 no. 3 doi:10.1128/microbiolspec.GPP3-0034-2018

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