Chapter 17 : New Therapeutic Developments against Shiga Toxin-Producing

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Shiga toxin (Stx)-producing (STEC) colonizes the intestine and causes hemorrhagic colitis. STEC encodes a variety of colonization factors, but a significant subset of STEC, the enterohemorrhagic (EHEC) strains, have the locus of enterocyte effacement (LEE), the products of which allow the bacteria to intimately adhere to and form attaching and effacing lesions on intestinal tissue. The O157:H7 strains, which are responsible for the majority of large outbreaks due to STEC infection, are members of the EHEC group. All STEC strains make one or more Stxs; these pathogens may produce two immunologically distinct but highly similar Stxs, Stx1 and Stx2. These toxins are briefly described in the section on therapeutics targeted to the Stxs.

Citation: Melton-Celsa A, O’Brien A. 2015. New Therapeutic Developments against Shiga Toxin-Producing , p 361-380. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0013-2013
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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.

Citation: Melton-Celsa A, O’Brien A. 2015. New Therapeutic Developments against Shiga Toxin-Producing , p 361-380. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. 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).

Citation: Melton-Celsa A, O’Brien A. 2015. New Therapeutic Developments against Shiga Toxin-Producing , p 361-380. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0013-2013
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Therapies directed against STEC, the Stx receptor, Stx function, or the cellular response to Stx

Citation: Melton-Celsa A, O’Brien A. 2015. New Therapeutic Developments against Shiga Toxin-Producing , p 361-380. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EHEC-0013-2013

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