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New Therapeutic Developments against Shiga Toxin-Producing

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  • Authors: Angela R. Melton-Celsa1, Alison D. O'Brien2
  • Editors: Vanessa Sperandio3, Carolyn J. Hovde4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; 2: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; 3: University of Texas Southwestern Medical Center, Dallas, TX; 4: University of Idaho, Moscow, ID
  • Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.EHEC-0013-2013
  • Received 10 July 2013 Accepted 21 August 2013 Published 12 September 2014
  • Angela R. Melton-Celsa, angela.melton-celsa.ctr@usuhs.edu
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  • Abstract:

    Shiga toxin (Stx)-producing (STEC) is an etiologic agent of bloody diarrhea. A serious sequela of disease, the hemolytic uremic syndrome (HUS) may arise in up to 25% of patients. The development of HUS after STEC infection is linked to the presence of Stx. STEC strains may produce one or more Stxs, and the Stxs come in two major immunological groups, Stx1 and Stx2. A multitude of possible therapeutics designed to inhibit the actions of the Stxs have been developed over the past 30 years. Such therapeutics are important because antibiotic treatment of STEC infections is contraindicated due to an increased potential for development of HUS. The reason for the increased risk of HUS after antibiotic treatment is likely because certain antibiotics induce expression of the Stxs, which are generally associated with lysogenic bacteriophages. There are a few potential therapeutics that either try to kill STEC without inducing Stx expression or target gene expression within STEC. However, the vast majority of the treatments under development are designed to limit Stx receptor generation or to prevent toxin binding, trafficking, processing, or activity within the cell. The potential therapies described in this review include some that have only been tested in vitro and several that demonstrate efficacy in animals. The therapeutics that are currently the furthest along in development (completed phase I and II trials) are monoclonal antibodies directed against Stx1 and Stx2.

  • Citation: Melton-Celsa A, O'Brien A. 2014. New Therapeutic Developments against Shiga Toxin-Producing . Microbiol Spectrum 2(5):EHEC-0013-2013. doi:10.1128/microbiolspec.EHEC-0013-2013.

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/content/journal/microbiolspec/10.1128/microbiolspec.EHEC-0013-2013
2014-09-12
2017-10-24

Abstract:

Shiga toxin (Stx)-producing (STEC) is an etiologic agent of bloody diarrhea. A serious sequela of disease, the hemolytic uremic syndrome (HUS) may arise in up to 25% of patients. The development of HUS after STEC infection is linked to the presence of Stx. STEC strains may produce one or more Stxs, and the Stxs come in two major immunological groups, Stx1 and Stx2. A multitude of possible therapeutics designed to inhibit the actions of the Stxs have been developed over the past 30 years. Such therapeutics are important because antibiotic treatment of STEC infections is contraindicated due to an increased potential for development of HUS. The reason for the increased risk of HUS after antibiotic treatment is likely because certain antibiotics induce expression of the Stxs, which are generally associated with lysogenic bacteriophages. There are a few potential therapeutics that either try to kill STEC without inducing Stx expression or target gene expression within STEC. However, the vast majority of the treatments under development are designed to limit Stx receptor generation or to prevent toxin binding, trafficking, processing, or activity within the cell. The potential therapies described in this review include some that have only been tested in vitro and several that demonstrate efficacy in animals. The therapeutics that are currently the furthest along in development (completed phase I and II trials) are monoclonal antibodies directed against Stx1 and Stx2.

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FIGURE 1

Induction of the -encoding phage by antibiotics such as ciprofloxacin. Subinhibitory concentrations of some antibiotics induce the lysogenic phage to enter the lytic cycle, and as consequence, -bacteriophage are made and released. Furthermore, 10- to 100-fold more toxin is made and released from the cell. doi:10.1128/microbiolspec.EHEC-0013-2013.f1

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.EHEC-0013-2013
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FIGURE 2

Cellular trafficking of Stx and points in the pathway where therapeutics function. Therapeutics can interfere with Stx action at several points as it traffics into and through the cell. The steps in toxin trafficking are briefly diagramed above and outlined here. The toxin first binds (B) to the receptor Gb3. The toxin/Gb3 complex is taken up (U) by both clathrin-dependent and -independent mechanisms, and then traffics (T) from the early endosome to the late endosome to the trans-Golgi apparatus. Within the Golgi the toxin A subunit is nicked (N), but the toxin remains intact due to a disulfide bond between the A and A subunits. The nicked toxin continues to traffic (T) along the retrograde pathway to the endoplasmic reticulum. The disulfide bond in the A subunit is reduced (R) within the endoplasmic reticulum and the A subunit enters the cytoplasm where it exerts its enzymatic (E) attack and depurinates the ribosome. The action of the toxin within the cell can lead to a ribotoxic stress response (RSR) and apoptosis (APOP). doi:10.1128/microbiolspec.EHEC-0013-2013.f2

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.EHEC-0013-2013
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Tables

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TABLE 1

Therapies directed against STEC, the Stx receptor, Stx function, or the cellular response to Stx

Source: microbiolspec September 2014 vol. 2 no. 5 doi:10.1128/microbiolspec.EHEC-0013-2013

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