Molecular Biology of Escherichia coli Shiga Toxins’ Effects on Mammalian Cells

Abstract

Shiga toxins (Stxs), syn. Vero(cyto)toxins, are potent bacterial exotoxins and the principal virulence factor of enterohemorrhagic Escherichia coli (EHEC), a subset of Shiga toxin-producing E. coli (STEC). EHEC strains, e.g., strains of serovars O157:H7 and O104:H4, may cause individual cases as well as large outbreaks of life-threatening diseases in humans. Stxs primarily exert a ribotoxic activity in the eukaryotic target cells of the mammalian host resulting in rapid protein synthesis inhibition and cell death. Damage of endothelial cells in the kidneys and the central nervous system by Stxs is central in the pathogenesis of hemolytic uremic syndrome (HUS) in humans and edema disease in pigs. Probably even more important, the toxins also are capable of modulating a plethora of essential cellular functions, which eventually disturb intercellular communication. The review aims at providing a comprehensive overview of the current knowledge of the time course and the consecutive steps of Stx/cell interactions at the molecular level. Intervention measures deduced from an in-depth understanding of this molecular interplay may foster our basic understanding of cellular biology and microbial pathogenesis and pave the way to the creation of host-directed active compounds to mitigate the pathological conditions of STEC infections in the mammalian body.

The Role of Escherichia coli Shiga Toxins in STEC Colonization of Cattle

“…In this review, the original designations in the cited publications, i.e., Stx1 and Stx2, are used. The second group comprises the prototypic Stx2 (also referred to as Stx2a) and its variants (as reviewed in [8]). Antisera against variants are partially cross-protective within but not between toxin groups [9].…”

The Impact of Plasma Membrane Lipid Composition on Flagellum-Mediated Adhesion of Enterohemorrhagic Escherichia coli

“…To reach the plasma membrane, bacterial flagella need to go through the mucus barrier, which is organized in two parts: an outer “loose” layer and an inner “firmly” attached layer ( 40 – 42 ). Different strategies can be used by enteropathogenic bacteria to overcome this barrier, such as the use of mucin-degrading enzymes ( 43 , 44 ), near surface swimming and mucus breaches ( 45 ), and Shiga toxin (Stx) production by Shiga toxin-producing E. coli to damage the intestinal barrier ( 46 ). Until recently, only a few studies have paid attention to enteric pathogen infection and plasma membrane lipid content during host invasion ( 36 ).…”

Shiga toxin remodels the intestinal epithelial transcriptional response to Enterohemorrhagic Escherichia coli

“…The 'ribotoxic stress response' to Stx-mediated cellular damage leads to the upregulation of a variety of genes and production of proteins which modulate the immune response (23,25,26). Purified Stx promotes the production of transcription factors (including JUN and FOS) and inflammatory cytokines (CCL2, CCL3, CCL4, CCL5, CSF2, CSF3, CXCL1, CXCL2, CXCL3, CXCL5, CXCL8, IL10, IL1αβ, IL6, TNFα) in cultured epithelial and immune cells (42,41,43,22,40,29,(44)(45)(46)(47)26). We found that several of these genes, including JUN, FOS, CCL4, CXCL8, and IL1A were differentially expressed in WT vs ∆∆stx infected colons; thus, Stx by itself, in the absence of additional EHEC-derived factors may account for a subset of the transcriptional changes we identified in the colonic epithelium of animals infected with the WT strain.…”

“…Samples from WT infection had higher levels of transcripts for F3, a gene which encodes the initiator of the clotting cascade, MMPs and SERPINs, which are proteases that regulate the processing of coagulation cascade proteins, as well as urokinase and the urokinase receptor, which regulate fibrin deposition. Stx is known to cause thrombosis in vascular beds outside of the GI tract, and has been investigated in the kidney microvasculature (26,71,72), but comparatively few studies have focused on Stx-linked coagulation in the intestine.…”

“…Stxs are potent AB5 subunit exotoxins which are thought to bind to the host cell surface glycosphingolipid globotriaosylceramide (Gb3). Once internalized into the eukaryotic cell cytosol, Stx catalyzes a site-specific depurination of the 28s rRNA, which leads to inhibition of protein synthesis and triggers the ribotoxic stress response, production of cytokines, and cell death (21)(22)(23)(24)(25)(26)(27). Absorption of Stx into the blood results in its systemic circulation and damage to endothelial cells, particularly in the renal microvasculature, leading to the characteristic findings of HUS, including renal failure and hemolysis.…”