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EcoSal Plus

Domain 8:

Pathogenesis

Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents

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  • Authors: A. R. Melton-Celsa1, M. J. Smith2, and A. D. O’Brien3
  • Editor: Michael S. Donnenberg4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; 2: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; 3: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; 4: University of Maryland, School of Medicine, Baltimore, MD
  • Received 05 October 2004 Accepted 15 December 2004 Published 29 March 2005
  • Address correspondence to A. D. O’Brien aobrien@usuhs.mil
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  • Abstract:

    The Shiga toxins (Stxs), also known as Vero toxins and previously called Shiga-like toxins, are a family of potent protein synthesis inhibitors made by type 1 and some serogroups of that cause bloody diarrhea in humans. Stxs act as virulence factors for both and and contribute to the disease process initiated by those organisms both directly and indirectly. A handful of methods exist for toxin purification, and the toxins can now even be purchased commercially. However, the Stxs are now classified as select agents, and specific rules govern the distribution of both the toxin and clones of the toxin. Toxin delivery into the host in type 1 is most likely aided by the invasiveness of that organism. Although the Stxs are made and produced by bacteria, they do not appear to act against either their host organism or other bacteria under normal circumstances, most likely because the A subunit is secreted from the cytoplasm as soon as it is synthesized and because the holotoxin cannot enter intact bacterial cells. The effectiveness of antibiotic therapy in patients infected with Stx-producing (STEC) such as O157:H7 as well as the potential risks of such treatment are areas of controversy. Several studies indicate that the course of the diarrhea stage of the disease is unaltered by antibiotic treatment. Several groups anticipate that a therapy that targets the Stxs is an important component of trying to alleviate disease caused by Stx-producing bacteria.

  • Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8

Key Concept Ranking

Bovine leukemia virus
0.50808173
Bacterial Virulence Factors
0.5030209
Tumor Necrosis Factor
0.4494178
Shiga Toxins
0.40727377
0.50808173

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/content/journal/ecosalplus/10.1128/ecosalplus.8.7.8
2005-03-29
2017-11-18

Abstract:

The Shiga toxins (Stxs), also known as Vero toxins and previously called Shiga-like toxins, are a family of potent protein synthesis inhibitors made by type 1 and some serogroups of that cause bloody diarrhea in humans. Stxs act as virulence factors for both and and contribute to the disease process initiated by those organisms both directly and indirectly. A handful of methods exist for toxin purification, and the toxins can now even be purchased commercially. However, the Stxs are now classified as select agents, and specific rules govern the distribution of both the toxin and clones of the toxin. Toxin delivery into the host in type 1 is most likely aided by the invasiveness of that organism. Although the Stxs are made and produced by bacteria, they do not appear to act against either their host organism or other bacteria under normal circumstances, most likely because the A subunit is secreted from the cytoplasm as soon as it is synthesized and because the holotoxin cannot enter intact bacterial cells. The effectiveness of antibiotic therapy in patients infected with Stx-producing (STEC) such as O157:H7 as well as the potential risks of such treatment are areas of controversy. Several studies indicate that the course of the diarrhea stage of the disease is unaltered by antibiotic treatment. Several groups anticipate that a therapy that targets the Stxs is an important component of trying to alleviate disease caused by Stx-producing bacteria.

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Figures

Image of Figure 1
Figure 1

The underlined regions indicate the processed signal sequence, dots depict identical residues, and green or red letters highlight conserved or nonconserved residues, respectively. The GenBank accession numbers are as follows: Stx1, M19473; Stx1c, AJ312232; Stx1d, AY170851. The sequences were aligned using the Align Plus 5 program, version 5.03 (Scientific & Educational Software, Durham, N.C.) following the global-ref alignment procedure ( 21 ) and the scoring matrix BLOSUM 62 ( 22 ).

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8
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Image of Figure 2
Figure 2

The underlined regions indicate the processed signal sequence, dots depict identical residues, and green or red letters highlight conserved or nonconserved residues, respectively. The GenBank accession numbers are listed in Fig. 1 . The sequences were aligned as for the Stx1 A subunit sequences in Fig. 1 .

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8
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Image of Figure 3
Figure 3

The underlined regions indicate the processed signal sequence, dots depict identical residues, green or red letters highlight conserved or nonconserved residues, respectively, and a red dash indicates a gap in the sequence. The GenBank accession numbers are as follows: Stx2, X07865; Stx2c, M59432; Stx2d, AF043627; Stx2dact, AF479829 (modified, February 2004); Stx2e, M21534; Stx2f, EAJ10730. The sequences were aligned as for Stx1 sequences in Fig. 1 .

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8
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Image of Figure 4
Figure 4

The underlined regions indicate the processed signal sequence, dots depict identical residues, green or red letters highlight conserved or nonconserved residues, respectively, and a red dash indicates a gap in the sequence. The GenBank accession numbers are listed in Fig. 3 . The sequences were aligned as for Stx1 sequences in Fig. 1 .

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8
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Image of Figure 5
Figure 5

The A subunits are in red, and the disulfide bridge is shown in yellow. The B subunits are depicted in orange, cyan, green, yellow, and blue. The figure was drawn with the programs MOLSCRIPT ( 85 ) and RASTER3D ( 86 ). The Protein Data Bank accession numbers are 1R4Q for Stx and 1R4P for Stx2.

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8
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Image of Figure 6
Figure 6

An STEC strain is depicted making phage particles and Stx at the same time. The toxin (shown as a red triangle [A subunit] with a purple star [B subunit]) emerges from the bacterium at the same time as the -converting phage (green).

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8
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Figure 7

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8
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Figure 8

In step 1, the toxin binds to Gb, during step 2 the toxin/Gb complex enters the cell through clathrin-coated pits and merges with the Golgi (step 3), and finally, in step 4, just the A subunit launches into the cytoplasm to attack the ribosome. The cell nucleus is shown as a solid black circle (not to scale).

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8
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Tables

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Table 1

Stx types, distinguishing feature compared with prototype, and location of toxin-encoding operon

Citation: Melton-Celsa A, Smith M, O’Brien A. 2005. Shiga Toxins: Potent Poisons, Pathogenicity Determinants, and Pharmacological Agents, EcoSal Plus 2005; doi:10.1128/ecosalplus.8.7.8

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