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Review
. 2019 Apr 9;11(4):212.
doi: 10.3390/toxins11040212.

Roles of Shiga Toxins in Immunopathology

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Free PMC article
Review

Roles of Shiga Toxins in Immunopathology

Moo-Seung Lee et al. Toxins (Basel). .
Free PMC article

Abstract

Shigella species and Shiga toxin-producing Escherichia coli (STEC) are agents of bloody diarrhea that may progress to potentially lethal complications such as diarrhea-associated hemolytic uremic syndrome (D+HUS) and neurological disorders. The bacteria share the ability to produce virulence factors called Shiga toxins (Stxs). Research over the past two decades has identified Stxs as multifunctional toxins capable of inducing cell stress responses in addition to their canonical ribotoxic function inhibiting protein synthesis. Notably, Stxs are not only potent inducers of cell death, but also activate innate immune responses that may lead to inflammation, and these effects may increase the severity of organ injury in patients infected with Stx-producing bacteria. In the intestines, kidneys, and central nervous system, excessive or uncontrolled host innate and cellular immune responses triggered by Stxs may result in sensitization of cells to toxin mediated damage, leading to immunopathology and increased morbidity and mortality in animal models (including primates) and human patients. Here, we review studies describing Stx-induced innate immune responses that may be associated with tissue damage, inflammation, and complement activation. We speculate on how these processes may contribute to immunopathological responses to the toxins.

Keywords: Shiga toxin types 1 and 2; Shiga toxin-producing Escherichia coli; Shiga toxins; bacterial toxins; hemolytic uremic syndrome; immunopathology.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Crystal Structure of Shiga toxins. A. Shiga toxin subtype 1a holotoxin (PDB #1DM0). B. Shiga toxin subtype 2a holotoxin (PDB # 1R4P). C. Shiga toxin subtype 1a B-subunits depicted with potential Gb3 receptor interactions (PDB #1BOS). D. Shiga toxin subtype 2a B-subunits depicted with potential Gb3 receptor interactions (PDB #1R4P, deletion of A-subunit). Toxin A-subunits are shown in dark blue in panels A and B. Individual B-subunits are shown in different colors in all panels. PDB files of all structures were obtained from RCSB PDB (www.rcsb.org) and compile PDB files with Chimera 1.10.2 (UCSF Chimera, www.cgl.ucsf.edu/chimera). Reproduced from reference [25]. 2016, MDPI.
Figure 2
Figure 2
Shiga toxin-induced immunopathology. Shiga toxins may cross the intestinal epithelial cell barrier by mechanisms involving M-cell uptake, transcellular transport, or paracellular transport. Once in the submucosa, the toxins may directly damage the intestinal microvasculature and elicit cytokine and chemokine production by resident macrophages. Macrophage activation results in the infiltration of neutrophils and monocytes which may further exacerbate tissue damage. Neutrophils and monocytes may also act as “carrier” cells to transport toxins in the bloodstream. Once in microvessels, such as glomeruli, that are rich in the toxin receptor, Gb3, the toxins may be transferred from the carrier cells to damage glomerular endothelial cells and tubular epithelial cells. The localized production of cytokines may up-regulate the expression of toxin receptors on some cell types, and activation of the complement cascade may further damage target organs.

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