Abstract
Shiga toxins (Stxs) produced by Shiga toxin-producing bacteria Shigella dysenteriae serotype 1 and select serotypes of Escherichia coli are primary virulence factors in the pathogenesis of hemorrhagic colitis progressing to potentially fatal systemic complications, such as hemolytic uremic syndrome and central nervous system abnormalities. Current therapeutic options to treat patients infected with toxin-producing bacteria are limited. The structures of Stxs, toxin-receptor binding, intracellular transport and the mode of action of the toxins have been well defined. However, in the last decade, numerous studies have demonstrated that in addition to being potent protein synthesis inhibitors, Stxs are also multifunctional proteins capable of activating multiple cell stress signaling pathways, which may result in apoptosis, autophagy or activation of the innate immune response. Here, we briefly present the current understanding of Stx-activated signaling pathways and provide a concise review of therapeutic applications to target tumors by engineering the toxins.
Highlights
Shiga toxin (Stx) is a protein exotoxin expressed by the Gram-negative bacteria Shigella dysenteriae serotype 1
Many types of cancer cells overexpress Gb3 on their surface, and the binding of toxins or the non-toxic pentameric Stx B-subunits coupled to anti-cancer agents has been explored for targeted cancer therapeutics [51,52,53,54] This paper will provide a concise review of the multi-functionality of Stxs
The precise location of Gb3 in the mouse and human CNS is controversial, and unlike Stx-mediated renal programmed cell death, apoptotic neuropathogenesis induced by Stxs has not been extensively examined, rabbit neurons appear to be susceptible to Stx-induced apoptosis [126]
Summary
Shiga toxin (Stx) is a protein exotoxin expressed by the Gram-negative bacteria Shigella dysenteriae serotype 1. In 2011, a widespread outbreak of gastroenteritis occurred in Europe associated with the ingestion of STEC-contaminated fenugreek or lentil sprouts [18] This outbreak was problematic for two reasons: (i) the causative agent was E. coli O104:H4, a serotype previously characterized as an enteroaggregative E. coli; and (ii) a high percentage of patients with diarrhea subsequently developed HUS (845/3816 cases) [18,19]. Stx2-containing MVs were detected adjacent to or within glomerular endothelial cells in a renal cortical biopsy from an HUS patient [34] Taken together, these findings suggest that once in the microvasculature serving target organs (primarily the kidneys and brain), the toxins may transfer from leukocytes or MVs associated with leukocytes to susceptible endothelial cells via high-affinity interactions with a membrane glycolipid receptor, globotriaosylceramide (Gb3 , known as CD77 or Pk blood group antigen). Many types of cancer cells overexpress Gb3 on their surface, and the binding of toxins or the non-toxic pentameric Stx B-subunits coupled to anti-cancer agents has been explored for targeted cancer therapeutics [51,52,53,54] This paper will provide a concise review of the multi-functionality of Stxs
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