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.
Highlights
Enterohemorrhagic Escherichia coli (EHEC), a subset of Shiga toxin-producing E. coli (STEC), are food-borne pathogens that can evoke life-threatening diseases, such as hemorrhagic colitis (HC) and hemolytic-uremic syndrome (HUS), in humans [1]
Despite the fact that viable bacteria were occasionally found at necropsy in mesenteric lymph nodes in natural hosts [6], STEC cannot be detected in extra-intestinal tissues in the course of systemic disease manifestations [7,8]
Evidence exists that Stx2-containing microvesicles play a pivotal role in transport and transfer of Shiga toxins (Stxs) in vivo and are even transferred from cell to cell [34], suggesting that Gb3-independent targeting of host cells is a yet under-appreciated pathogenic mechanism, presumably with significant implications for the course of STEC-associated diseases
Summary
Enterohemorrhagic Escherichia coli (EHEC), a subset of Shiga toxin-producing E. coli (STEC), are food-borne pathogens that can evoke life-threatening diseases, such as hemorrhagic colitis (HC) and hemolytic-uremic syndrome (HUS), in humans [1]. (AE) lesions, leading to tight association of single bacteria or small size colonies to the intestinal epithelial cells These alterations are primarily independent of the Stxs‘ effects [13] and encoded by the locus of enterocyte effacement (LEE) in the STEC chromosome [14,15]. Therapeutic options to treat human patients suffering from STEC-associated diseases are still limited at present and, if available [45], not directly counteracting the detrimental effects of the Stxs. The recent unprecedented HUS outbreak in Europe 2011, caused by an unusual hybrid strain of the serotype O104:H4, which lacked the LEE locus [3], stresses the fact that Stxs are the principal virulence factors and the only common denominator of STEC strains posing a threat to human health. Irrespective of significant species and tissue differences in cell susceptibility and tissue distribution of receptors, a comprehensive knowledge of the molecular mechanisms of Stx–host interactions needs to be considered to mitigate human health risk
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