Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

Abstract

The severity of human infection by one of the many Shiga toxin-producing Escherichia coli (STEC) is determined by a number of factors: the bacterial genome, the capacity of human societies to prevent foodborne epidemics, the medical condition of infected patients (in particular their hydration status, often compromised by severe diarrhea), and by our capacity to devise new therapeutic approaches, most specifically to combat the bacterial virulence factors, as opposed to our current strategies that essentially aim to palliate organ deficiencies. The last major outbreak in 2011 in Germany, which killed more than 50 people in Europe, was evidence that an effective treatment was still lacking. Herein, we review the current knowledge of STEC virulence, how societies organize the prevention of human disease, and how physicians treat (and, hopefully, will treat) its potentially fatal complications. In particular, we focus on STEC-induced hemolytic and uremic syndrome (HUS), where the intrusion of toxins inside endothelial cells results in massive cell death, activation of the coagulation within capillaries, and eventually organ failure.

Keywords: Escherichia coli; Shiga toxin; hemolytic uremic syndrome; thrombotic microangiopathy.

Figure 1

Nomenclature of thrombotic microangiopathies and pathogenic Escherichia coli, including distribution of serotypes in reported cases in 2012–2014 in Europe. Abbreviations—TMAs: thrombotic microangiopathies; HELLP: hemolysis, elevated liver enzymes and low platelets syndrome; TTP: thrombotic thrombocytopenic purpura; HUS: hemolytic uremic syndrome; aHUS: atypical hemolytic uremic syndrome; STEC-HUS: Shiga toxin Escherichia coli-associated hemolytic uremic syndrome; ST+: Shiga toxin-producing bacteria; EHEC: enterohemorrhagic E. coli (represent STEC serotypes pathogenic to humans); LEE+: locus of enterocyte effacement-expressing bacteria, E. coli expressing both ST and LEE genes (“typical STEC”); AEEC: attaching and effacing E. coli; EPEC: enteropathogenic E. coli. The distribution of EHEC serotypes corresponds to the reported cases in Europe between 2012 and 2014 [4].

Figure 2

Proportional circles map of major outbreaks of enterohemorrhagic E. coli O157 and non-O157 reported in the literature (1985–2017). Published reports of outbreaks including more than 5 STEC-HUS cases are represented. The sizes of violet and red circles are proportional to the numbers of cases of diarrhea (when available) and hemolytic uremic syndrome reported in each outbreak, respectively, using perceptual scaling. Dashed circles represent outbreaks caused by non-O157 strains.

Figure 3

Intracellular trafficking and cytotoxicity of Shiga toxin. A simplified depiction of Shiga toxin intracellular trafficking and mechanisms of toxicity. 1: Shiga toxins consist of a monomeric enzymatically active A subunit, non-covalently linked to a pentameric B subunit. The B subunit binds to the glycosphingolipid globotriaosylceramide (Gb3), present in lipid rafts on the surface of the target cell. 2: Shiga toxin and its receptor are internalized (endocytosis), and Shiga toxin is activated through cleavage of the A subunit into 2 fragments by the protease furin (represented by a blue crescent). Disulfide bonds keep the 2 fragments together in the endosome. 3: Shiga toxin avoids the lysosomal pathway and is directed towards the endoplasmic reticulum (retrograde transport) where the disulfide bound is reduced. 4: The A1 subunit translocates into the cytoplasm (anterograde transport) where it can exert its cytotoxic effects. 5: The processed A1 fragment cleaves one adenine residue from the 28S RNA of the 60S ribosomal subunit, thus inhibiting protein synthesis and triggering the ribotoxic and endoplasmic reticulum stress responses. 6: In addition to its ribotoxic effect, Shiga toxin activates multiple stress signaling and apoptotic pathways, and is responsible for the production of inflammatory cytokines by target cells.

Figure 4

Timeframe of the development and evolution of STEC-HUS, with the theoretical window of diagnostic tests. The timeframe and proportions represented here are based on median values and are highly variable, depending on strain, epidemiological and individual patient characteristics.