Shiga toxin in enterohemorrhagic E.coli: regulation and novel anti-virulence strategies

Abstract

Enterohemorrhagic Escherichia coli (EHEC) are responsible for major outbreaks of bloody diarrhea and hemolytic uremic syndrome (HUS) throughout the world. The mortality associated with EHEC infections stems from the production and release of a potent Shiga toxin (Stx) by these bacteria. Stx induces cell death in endothelial cells, primarily in the urinary tract, causing HUS. Stx was first described in Shigella dysenteriae serotype I by Kiyoshi Shiga and was discovered later in EHEC. Multiple environmental cues regulate the expression of Stx, including temperature, growth phase, antibiotics, reactive oxygen species (ROS), and quorum sensing. Currently, there is no effective treatment or prophylaxis for HUS. Because antibiotics trigger Stx production and their use to treat EHEC infections is controversial, alternative therapeutic strategies have become the focus of intense research. One such strategy explores quorum sensing inhibitors as therapeutics. These inhibitors target quorum sensing regulation of Stx expression without interfering with bacterial growth, leading to the hypothesis that these inhibitors impose less selective pressure for bacteria to develop drug resistance. In this review, we discuss factors that regulate Stx production in EHEC, as well as novel strategies to prevent and/or minimize the development of HUS in infected subjects.

Keywords: enterohemorrhagic E. coli (EHEC); hemolytic uremic syndrome (HUS); shiga toxin.

Figure 1

Mechanism of action of Shiga toxin (Stx). Stx is constituted by a pentamer of B subunits bound to a catalytic A subunit. The B subunits bind to globotriaosylceramide (Gb3) expressed by some eukaryotic cells (1) Stx is internalized by endocytosis (2) Subsequently, Stx undergoes retrograde transport to the trans-Golgi network (TGN) (3) and then to the endoplasmic reticulum (ER) (4) In the ER, Stx encounters its target, the ribosome, inactivating it (4) As a consquence, Stx inhibits protein synthesis, causing cell death by apoptosis.

Figure 2

Regulation of Shiga toxin expression by the phage cycle. The cI repressor bound to operator sites O_L and O_R inhibitis transcription from the promoters P_L and P_R. The presence of terminator downtream of P_R' inhibits transcription of stxAB and the phage remains quiescent. When SOS response is triggered, RecA cleaves cI, relieving P_R repression and expression of antiterminators N and Q. Antiterminator Q binds P_R' leading to transcription of stxAB genes with the late phage genes.

Figure 3

Inhibition of signal transduction by LED209. LED209 prevents autophosphorylation of the adrenergic sensor QseC, which is required to activate the expression of genes involved in colonization of the intestinal epitheliu.