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Shiga (Vero)-toxigenic Escherichia coli: epidemiology, virulence and disease.

INTRODUCTION

Shiga-toxigenic Escherichia coli (STEC), also known as Verotoxigenic E. coli (VTEC), are a toxin-producing subset of a normally commensal enteric bacterium. This subset is recognised to be a significant contributor to diarrhoeal disease worldwide. Much of the epidemiological and diagnostic effort regarding STEC is directed towards serogroup O157, because of its common association with severe forms of gastrointestinal disease, including haemorrhagic colitis (HC), and extra-intestinal disease, such as haemolytic uraemic syndrome (1, 2).

In recent years, international researchers and surveillance networks have noted increases in the number of cases of diarrhoea and more severe symptoms caused by STEC belonging to serogroups other than O157 (collectively referred to as 'non-O157') (3). Non-O157 STEC contribute to a significant proportion of STEC-related illness in developed countries (4), with some strains considered to have a pathogenic potential comparable to that of the most virulent O157 serotype, O157:H7 (4, 5). Much of the disease burden presented by non-O157 E. coli remains under-reported in many countries (2, 3), mainly due to limitations in popular diagnostic techniques to detect these serotypes (4, 5). However, this is changing with the introduction of molecular assays targeting Stx genes (4). E. coli O157:H7 related disease is notifiable in New Zealand, and national data accumulated since the first case in 1993 indicates that the incidence of all reported STEC has been steadily increasing, as shown in Figure 1 (6).

The purpose of this review is to trace the history of STEC, describe the relationship between major virulence factors and pathology, comment on disease course and current therapy, and discuss the epidemiology of these pathogens in New Zealand and elsewhere, highlighting distinctive differences.

HISTORY

Many major E. coli pathotypes have emerged overtime through the transfer of virulence factors from other bacterial species by way of mobile genetic elements such as pathogenicity islands, transposons, and plasmids (7). The different pathotypes associated with human diarrhoea have been extensively reviewed by Croxen et al (8) and are summarised in Table 1. There is uneven geographical distribution of some of these pathotypes; for example, enterotoxigenic E. coli (ETEC) are particularly problematic in developing countries (8). On the other hand, STEC have been reported to occur world-wide (9).

The role of STEC in human health emerged in 1983, when Karmali et al (10), discovered a substance acutely lethal to African green monkey kidney (Vero) cells in the filtered stools of children suffering from haemolytic uraemic syndrome. Vero cytotoxic E. coli recovered from patient stool samples belonged to semigroups O26, O111, O113 and O157 (10). This study was published in the same year as another investigation by Riley et al, where an unusual serotype of E. coli, expressing the somatic (O) antigen 157 and the flagellar (H) antigen 7, was reckoned to be the cause of bloody diarrhoea (11). Subsequent investigations confirmed the link between STEC infection and cases of diarrhoea, haemorrhagic colitis, haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura (12), and also revealed there are two main types of Shiga toxin, Stx1 and Stx2. Stx1 is antigenically similar to Shiga toxin produced by Shigella dysenteriae while Stx 2 is less closely related and antigenically distinct (12). The genes encoding these toxins (stx1 and stx2) appearto be highly mobile.

According to Law (13), STEC O157:H7 arose from the enteropathogenic serotype E. coli (EPEC) O55:H7. The chromosomes of enteropathogenic E. coli encode the cell adhesin intimin, a virulence factor also important in STEC. Originally, an E. coli O55:H7 is believed to have been infected with a stx2 carrying bacteriophage (a virus which can infect bacteria) then later acquired the large virulence plasmid pO157 and a gene encoding the O157 antigen. This progenitor is thought to have divided into two lineages: 1. non-motile, sorbitol fermenting Stx 2 producing strains seen in Germany and parts of Eastern Europe; 2. sorbitol non-fermenting strains producing both Stx1 and Stx2, the former toxin having crossed over from Shigella dysenteriae. The next step along the evolutionary pathway was the loss of the enzyme beta-glucuronidase to give the common beta-glucuronidase/MUG negative, sorbitol non-fermenting O157:H7 clone. Non-O157 STEC have not been so extensively studied, but from the wide diversity of E. coli semigroups found to harbour Stx, it can be surmised that transfer of stx by bacteriophages is a common event and occurred quite recently in an O104:H4 strain (13,14). Although the timescale for these events is not known, a large, post-war outbreak of diarrhoea with symptoms of haemolytic uraemic syndrome in the USA suggests they occurred prior to the 1950s (15).

VIRULENCE AND PATHOLOGY

In STEC, Stx1 and Stx2 are encoded on two mobile genetic elements (H19B and 933W, respectively) derived from bacteriophages (16). These prophages have the ability to insert themselves into the chromosomal DNA of E. coli through the action of recombinase enzymes (17). The prophages permit the host E. coli to express Stx and can also multiply and excise themselves from E. coli genomes (18-20). The toxins expressed form a protein complex composed of two subunits; a single A subunit attached to five identical B subunits (21). The B subunit pentamer component of the toxin binds to glycosphingolipid globotriosylceramide (Gb3) receptors of absorptive villi and Paneth cells in the mammalian intestine, and globotetraosylceramide (Gb4) surface receptors in renal glomerular cells and brain endothelia (18, 21-23). Binding by B subunits promotes the internalisation of the toxin complex in an early endosome. A proposed alternative route for Stx entry is through bacterial invasion of the host cell (24). From the endosome, the toxin is transported to the trans-Golgi network, then through the Golgi apparatus to the endoplasmic reticulum, where the released A subunit induces a number of host cell responses including inhibition of protein synthesis, apoptosis (programmed cell death), autophagy (degradation of cellular components) and increases in chemokine and cytokine production (21, 23, 24) (Figure 2). The toxins cause bloody and non-bloody diarrhoea through the killing of intestinal endothelial cells either directly, or indirectly through inducing mesenteric ischaemia in the regional vasculature (2). The toxins are also able to translocate across the gastrointestinal endothelia and enter the systemic circulation, causing a host of pathological thrombotic and immunomodulatory effects on both the renal glomerulus and systemic microvasculature (21, 23). The mechanism by which the toxins traverse to the circulation is unknown (25), and the systemic effects are not usually accompanied by bacteraemia (26).

Stx2 has at least a 100-fold higher toxicity against renal endothelial cells than Stx1 (1,21) due to differences in the DNA sequences encoding the toxin components (27). As a result, Stx2 is the variant most often associated with clinical cases of STEC and the progression of such cases to haemorrhagic colitis and haemolytic uraemic syndrome (21,27). Stx2 is also noted to have a number of subvariants (Stx2, stx2c2, stx2d, stx2e, and stx2f) each with varying toxicity (28, 29). Perhaps unsurprisingly, O157 serotypes associated with clinical symptoms are generally found to produce Stx2, usually in preference to Stx1. Stx2 may occur in other semigroups but the frequency is lower than Stx1 (27, 30, 31).

A virulence factor that STEC and EPEC can have in common is the adherence factor intimin, which has the encoding sequence eaeA. Intimin is a bacterial outer membrane protein encoded within a chromosomal pathogenicity island referred to as the Locus of Enterocyte Effacement (LEE) (1). The LEE encodes a syringe-like type III secretion system, capable of injecting over 50 bacterial effector proteins directly into the cytosol of the human host cell (21, 32). In strains possessing LEE, intimin anchors bacteria to host cells (33, 34) facilitating injection of the effector proteins. These reshape the actin cytoskeleton of intestinal epithelial cells to form characteristic 10 pm pedestal formations on the cell surface, as shown in Figure 3 (33, 35). The close bacterium/host cell association formed by the components of the LEE mechanism are recognised to greatly aid in the delivery of Stx to enterocytes and the underlying mesenteric vasculature (33). Most of the strains isolated from outbreaks of haemorrhagic colitis and haemolytic uraemic syndrome, and those infections with more severe symptoms, typically express both Stx and intimin along with carriage of pO157 (30, 31, 36), and are usually designated as the pathotype enterohaemorrhagic E. coli (EHEC) (37). The tendency for haemolytic uraemic patients to form strong antibody responses to intimin and other LEE components underscores the importance of the adhesion determinant in advanced STEC infections (32).

The high virulence of serotype O157:H7 is attributed to Stx2 production, LEE and accessory virulence factors carried on a plasmid, pO157 (21,38). pO157 encodes putative virulence factors such as proteases, enterohaemolysin (ehx) and cell adhesins on a heterogeneous mix of prophages, transposons and genetic elements thought to have evolved to aid intestinal colonisation in cattle (21, 32, 39). However, haemolytic uraemic syndrome-causing strains do not consistently have the full complement of known virulence factors (37). A second large plasmid, pO113, is believed to encode other virulence factors which may allow LEE negative STEC to cause haemolytic uraemic syndrome (40).

DISEASE COURSE AND THERAPY

Due to the confluence of host and virulence factors, the clinical spectrum of STEC is appreciably broad and patient outcomes may be difficult to predict. Symptoms can range from asymptomatic or subclinical (and hence unreported) diarrhoea to severe haemorrhagic and neurological complications and death. Clinical cases of STEC infection typically present as self-limiting, with painful abdominal cramps and non-bloody diarrhoea that occur 1-8 days post ingestion (35, 41), but may progress to bloody diarrhoea without fever or raised leucocyte count after a further 2-7 days (21, 35). The progression to haemorrhagic colitis and haemolytic uraemic syndrome is difficult to predict (19), but is especially frequent in children <10 years of age (35, 42), the immunocompromised and the elderly, with the highest rates associated with EHEC ([stx.sup.+], [eaeA.sup.+]) and particularly O157 serotypes (21, 35). The rate of progression to haemorrhagic colitis and haemolytic uraemic syndrome is generally 10-15%, although this is subject to patient factors, the accessory virulence factors present, and the Stx variant expressed (18, 42, 43). Haemolytic uraemic syndrome is characterised by the onset of microangiopathic anaemia (damaged erythrocytes), thrombocytopenia and may be accompanied in adults by thrombotic thrombocytopenic purpura (a diffuse formation of microangiopathic thrombi, often with concurrent neurological abnormalities) (12, 44). Haemolytic uraemic syndrome is the clinical manifestation of Stx-induced damage of the kidney glomerular vasculature, and may even result in long term sequelae such as renal insufficiency and neurological aberrations (35). Overall, 3-5% of cases are fatal (21).

Generally, non-O157 infections have a milder course than that of O157:H7. In the latter, diarrhoea has a greater likelihood of being bloody (>90% chance with O157 vs 60%), abdominal cramping is usually more severe, and the need for hospitalisation (43% vs 18%) and progression to haemolytic uraemic syndrome (10-15% vs <10%) is more pronounced (3). Combined eae and stx2 carriage is regarded as a stronger predictor for bloody diarrhoea and haemolytic uraemic syndrome than the presence of serogroup O157 (45). The haemolytic uraemic syndrome that accompanies severe STEC infection can mimic other intestinal diseases such as Crohn's disease and induce elevated faecal calprotectin levels, while chronic STEC infections may result in irritable bowel syndrome (IBS) (21). Many physicians have an incomplete understanding of STEC infection and do not consider non-O157:H7 infection as part of a differential diagnosis (46). The clinical presentation of STEC infection may also potentially lead to confusion with other gastrointestinal disorders such as intussusception, appendicitis, inflammatory bowel disease (IBD), or infection with Clostridium, Shigella, Yersinia, Salmonella, or Campylobacter species (12, 19, 47, 48).

Treatments options for STEC infections are largely supportive, as antibiotics that induce DNA damage in E. coli have a tendency to activate a lysogenic SOS response in the Shiga prophage and cause upregulation of the expression of Stx (29). As a result, treatments involving quinolones, ciprofloxacin, in addition to anti-motility agents, are contraindicated in STEC infection, having been associated with increased incidences of progression to haemolytic uraemic syndrome (21, 26, 49). Parenteral volume expansion with liberal amounts of intravenous fluids (21, 50), particularly in conjunction with peritoneal dialysis is the recommended course for advanced cases of STEC infection (19, 25). Early administration of the monoclonal anti-Shiga toxin antibody Eculizumab is also recognised to increase platelet counts and limit toxin-mediated neurological effects (25, 50). The development of vaccines capable of stimulating a strong antibody response against pathogenic E. coli antigens such as intimin (29, 51), is currently ongoing, albeit hampered by the difficulty in finding an appropriate animal model (35).

EPIDEMIOLOGY

The global impact of STEC infection is difficult to estimate because of inconsistencies in reporting methods between countries and the varying prevalence of detected and undetected serotypes within such countries. A recent estimate, a meta-analysis of papers and databases of 21 countries, places the global number of acute STEC infections at approximately 2.8 million per year, with an estimated 3890 cases of haemolytic uraemic syndrome, 270 cases of end-stage renal disease, and 230 mortalities (52). STEC infections are usually sporadic and generally affect children and the elderly, with the typical source of infection being the ingestion of contaminated foodstuffs (35). The natural reservoir of STEC is the intestine and rectum of cattle, and the contamination of processed beef carcasses combined with modern mass distribution is recognised as the classic cause of larger outbreaks (1, 53, 54). STEC may also be carried by a variety of farmyard animals including sheep, goats, chickens, pigs and deer, with outbreaks traced to contact with these animals or consumption of improperly prepared foodstuffs (42, 55, 56).

World-wide, STEC outbreaks have also been associated with person-to-person spread, as well as contaminated or unpasteurised milk, juice, sprouts and other vegetables (43). The durability of STEC in bovine faecal matter and groundwater is thought to permit the spread of STEC to mass-produced crops via effluent run-off and exposures through environmental water sources (29, 51, 57, 58). Perhaps the most notable case of an outbreak of STEC infection was the 2011 O104:H4 outbreak in Germany, involving an especially virulent strain of non-O157 E. coli that caused over 4000 STEC illnesses, 908 cases of haemolytic uraemic syndrome and 90 deaths (49). The source of infection was ultimately traced to a batch of contaminated fenugreek sprouts (49), and although the strain did not employ intimin as its primary attachment factor (59), the outbreak served to highlight the contribution of non-O157 STEC to human disease in developed countries. Non-O157 STEC infection is usually dominated by the semigroups 026, 045, O103, O111, O121 and O145, which together typically comprise -70% of the non-O157 STEC infections in many countries and are well represented amongst isolates retrieved from sufferers of haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura and bloody diarrhoea (27, 31). These semigroups, known as the 'Big 6' possess many of the virulence factors and associations to complicated enteric disease seen in O157:H7 strains (5), although the dominant strain may vary from country to country (Table 2).The contribution of the 'Big 6' to STEC disease is noted to be underreported (3), and international data suggests that the proportion of STEC disease caused by non-O157 semigroups is increasing (3, 4, 60, 61). It's important to note that semigroup alone is not a determinant of virulence as carriage of virulence genes varies between strains ofthe same semigroup.

In New Zealand, the annual notification rate for all STEC infection has been increasing since 1997, with the highest number notified in the most recent Annual Surveillance Report produced by Environmental and Science Research (330 cases; 7.2/100,000 population) (6). However, this significant increase is most probably due to the introduction of PCR screening of all faecal samples in an Auckland laboratory (Figure 1) (6). Most STEC cases are unrelated or occur in small outbreaks confined to a family or geographic region with exposure to contaminated farmland or private water supplies as primary risk factors (62). Infection peaks in the summer months when outdoor activities increase (63). ESR identified common risk factors in 2015 as contact with pets, farm animals and manure (6).

The Enteric Reference Laboratory at ESR identified 53% of received STEC isolates as serotype O157:H7 in 2015, with the remainder confirmed as non-O157 E. coli (29.3%) or of undetermined serotype (17.7%) (6). In a recent qPCR study of over 500 diarrhoeic stool samples received by Southern Community Laboratories, Dunedin, the only STEC semigroups detected using molecular techniques were O103 and O157 (both in two patients). A further six stool samples from six patients were positive for stx but non-typable, indicating they did not belong to semigroup O157 or any of the 'Big 6' (63). This lack of dominance of the 'Big 6' semigroups among non-O157 STEC is compatible with previous studies of human cases, STEC types found in in retail meat and animal carriage and is likely related to agricultural practices in New Zealand (64-67).

CONCLUSIONS

E. coli O157:H7 was the first STEC to be discovered but it is now clear that non-O157 STEC are capable of causing disease, which can be severe if they produce Stx2 and encode intimin or other cell adherence factors. The roles of Stx, intimin and accessory gene products have been well described and a clear link to the pathology and clinical manifestations established. However, the virulence genotype(s) of the enterohaemorrhagic subset, EHEC, has not been fully defined and STEC strains are designated as EHEC mainly based on clinical associations. Some of the prophages encoding stx are able to infect other E. coli. This, and the potential mobility of other virulence factors, points to future evolutionary changes in the STEC pathotype (68). An example of this type of horizontal gene transfer is provided by the O104:H4 enteroaggregative E. coli strain, which acquired stx and caused a massive outbreak of illness in Europe, including haemolytic uraemic syndrome (69).

Compared to most other countries, there are distinctive differences in NZ with regard to the dominant risk factors and semigroups of non-O157 STEC. Elsewhere in the world food is the most significant transmission vehicle for O157 and the 'Big 6' semigroups, but in New Zealand STEC infection occurs with a greater diversity of semigroups mainly through contact with contaminated agricultural environments or animals. So far, New Zealand has not experienced the large STEC outbreaks seen in other countries, probably because of differences in food production and/or regulation of the industry. With few treatment options available, STEC represent an important and previously underestimated pathogen group. Due to the varying clinical picture, diagnosis can be difficult but it is anticipated that the adoption of molecular diagnostic techniques for STEC detection will lead to correct diagnosis and better reflect the true incidence of STEC infection.

ACKNOWLEDGEMENTS

Rowan Thomas thanks the University of Otago and Dunedin Basic Medical Sciences for Masters and Sandy Smith scholarships respectively. The authors thank Douglas McComish for construction of Figure 2 and the Otago Centre for Electron Microscopy for electron micrograph images (Figure 3).

AUTHOR INFORMATION

Rowan R Thomas, BMLSc MMLSc [1]

Mabel LH Gaastra, BSc PGDipSci, Medical Student [2]

Heather JL Brooks, BSc(Hons) PhD, Senior Lecturer and Course Director for Medical Laboratory Science [3]

[1] Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago

[2] Dunedin School of Medicine, University of Otago

[3] Department of Pathology, Dunedin School of Medicine, University of Otago

Correspondence: Dr Heather Brooks, Department of Pathology, University of Otago, PO Box 913, Dunedin 9054, New Zealand.

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Rowan R Thomas, Mabel LH Gaastra and Heather JL Brooks

Department of Pathology, University of Otago, Dunedin

Caption: Figure 1. Number of all STEC infections reported to ESR by community and hospital based diagnostic laboratories 1997-2015. The number of notifications of STEC infections has been increasing since 1997 (6).

Caption: Figure 2. Proposed mode of action of Shiga toxin. Shiga toxin binds to the host cell receptor Gb3 (globotriaosylceramide, [P.sup.k] blood group antigen). Following internalisation in an early endosome, the toxin is transported to the Golgi apparatus then to the endoplasmic reticulum where the dissociated A subunit inhibits protein synthesis by destroying the function of ribosomal RNA (28S subunit). The toxin A subunit is subsequently released into the cytosol. Host cell responses include autophagy (degradation of cell constituents), apoptosis (programmed cell death), ribotoxic and endoplasmic reticulum stress, and release of pro-inflammatory cytokines and chemokines (reviewed by Lee et al (24)).

Caption: Figure 3. Formation of actin pedestals. Formation of actin pedestals (a) due to the interaction of intimin with translocated intimin receptor (22). This is preceded by an initial loose attachment (b), then firm attachment with underlying effacement of the microvilli (c). Figure shows serogroup O111 Escherichia coli attached to the surface of Hep-2 tissue culture cells (prepared for transmission electron microscopy using standard fixation and osmium tetroxide staining by M. Gaastra).
Table 1. Diarrhoeagenic Escherichi coli pathotypes

E. coli pathotype    Acronym     Disease             eaeA, stx
                                                     genes *

Shiga-toxigenic/     STEC/EHEC   Watery diarrhoea,   [eaeA.sup.+/-],
Enterohaemorrhagic               haemorrhagic        [stx.sup.+]
                                 colitis,
                                 haemolytic
                                 uraemic
                                 syndrome

Enteropathogenic     EPEC        Watery diarrhoea    [eaeA.sup.+],
(typical/atypical)                                   [stx.sup.-]
([dagger])

Enteroinvasive       EIEC        Dysentery           [eaeA.sup.-],
([double dagger])                                    [stx.sup.-]

Enteroaggregative    EAEC syn.   Traveller's         [eaeA.sup.-],
                     EAggEC      diarrhoea,          [stx.sup.-]
                                 (haemolytic         (serotype
                                 uraemic syndrome)   O104:H4
                                                     [stx.sup.+])

Enterotoxigenic      ETEC        Persistent watery   [eaeA.sup.-],
                                 diarrhoea           [stx.sup.-]

Diffusely adherent   DAEC        Persistent watery   [eaeA.sup.-],
                                 diarrhoea in        [stx.sup.-]
                                 children (Crohn's
                                 in adults?)

* Important genetic markers of virulence for STEC and EPEC

([dagger]) Typical EPEC possess E. coli adherence factor plasmid
pEAF, atypical EPEC do not

([double dagger]) Closely related to Shigella spp.; S.
dysenteriae [stx.sup.+]

Table 2. Prevalent and predominant Shiga-toxigenic
Escherichia coli semigroups by country

Country/Continent   Prevalent            Predominant
                    serogroups           serogroup

United States       O157, O26, O111,     O157
of America          O103, O121, O45,
                    O145

Canada              O157, O55, O125,     O157
                    O26, O126, O128,
                    O18

South America       O1, O2, O15, O25,    Non-O157
                    O26, O49, O92, O11

United Kingdom      O157                 0157

Continental         O157, O26, O111,     Both O157 and
Europe              O104, O103, O128,    non-O157
                    O91, O113, O2, O9,
                    O145

Australia           O157, O111, O26      Both O157 and
                                         non-O157

Japan               O157, O26, O111      0157

Table adapted from Vanaja et al (41)
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Author:Thomas, Rowan R.; Gaastra, Mabel L.H.; Brooks, Heather J.L.
Publication:New Zealand Journal of Medical Laboratory Science
Article Type:Report
Geographic Code:8NEWZ
Date:Apr 1, 2018
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