Verotoxigenic<i>Escherichia coli</i>from animals, humans and foods: who's who?

Verocytotoxigenic (shigatoxigenic) and enterohaemorrhagic Escherichia coli, VTEC (STEC) and EHEC, produce a toxin active on Vero cells in vitro. VTEC and EHEC have been isolated from humans and different animal species, mainly ruminants and pigs. The verocytotoxins, also named shiga toxins (Stx), are active in vivo on the endothelial cells of the blood vessels of the gastro-intestinal mucosa, the kidneys, the brain, and other tissues of humans and piglets, leading to fluid leakage or haemorrhages. Conversely, their role in diseases of young ruminants remains unclear. Adult ruminants can also act as asymptomatic carriers of VTEC and EHEC strains similar to those causing diseases in humans. And they are incriminated as an important source of direct or indirect contamination of humans by the most famous EHEC strain belonging to the O157:H7 serotype, through faecal contamination of either foods of animal origin, or other foodstuffs (fruit, vegetables, etc.), or the environment. But dozens of non-O157 human and ruminant VTEC and EHEC strains with similar general and virulence-associated properties, have been described, whose epidemiology is much less well understood. The purpose of this review manuscript is to describe and compare the properties of human, ruminant and food VTEC and EHEC strains. Among the numerous classes of pathogenic Escherichia coli the verocytotoxigenic (or shigatoxigenic) strains have certainly the widest notoriety. Their names originate from the production of a toxin active on Vero cells in culture, which is also related to the shiga toxin (Stx) of Shigella dysenteriae type 1. Such verocytotoxigenic E. coli (VTEC) have been known for half a century in the pig industry, as the cause of oedema disease (ED) in recently weaned piglets. But until the early 1980s they were of little significance, if any, in human medicine. Why they have become so notorious in a few years in comparison with the other pathogenic strains of E. coli is certainly related to their high pathogenicity in humans, with potentially serious clinical outcomes and to their possible transmission to humans via foods of animal origin, especially ruminants. These particular E. coli strains have therefore rapidly become a major concern and study subject in human medicine, molecular biology and veterinary medicine. The purpose of this review is to (i) present the history and definitions of VTEC (ii) describe the current knowledge on their virulence properties and (iii) compare them based on their origin. This review manuscript is based on several review articles and books recently published in the medical, microbiological and veterinary fields (Ludwig and Goebel 1997; Scotland and Smith 1997; Hancock et al. 1998; Kaper et al. 1998a,b; Melton-Celsa and O'Brien 1998; Meng and Doyle 1998; Nataro and Kaper 1998; O'Brien and Kaper 1998; Paton and Paton 1998; Mainil 1999; Duffy et al. 2000; Blanco et al. 2001; Brown et al. 2001; De Boer and Heuvelink 2001; Gyles 2001; Schmidt et al. 2001; Tozzi et al. 2001; Koronakis and Hughes 2002; Thorpe et al. 2002) and on national and international scientific reports (Anonymous 2003; Vernozy-Rozand and Roze 2003). Other important past or recent research papers are also cited in the text. The history of VTEC follows two convergent paths. The first pathway began in 1977, when the production of a cytotoxin causing the death of Vero cells in culture (hence the name verocytotoxin) was reported for strains of E. coli isolated from humans suffering from diarrhoea and from piglets suffering of postweaning ED (Konowalchuk et al. 1977). A few years later, several human E. coli strains, including one strain previously studied by the group of Konowalchuk (strain H30) were reported to produce a similar cytotoxic effect on HeLa cells in culture, which could be neutralized by an immune serum produced against the Stx of S. dysenteriae type 1 (Stx), hence the name shiga-like toxin (O'Brien et al. 1982). During the following years, the identity of these two types of toxins was recognized, as was their heterogeneity. The nomenclature ‘verocytotoxin and VTEC’ has been used since then by British and Canadian teams, while the nomenclature ‘shiga-like toxins and shiga-like toxin-producing E. coli’ was used by the American teams until 1996, when the names shiga toxins and shigatoxigenic E. coli (STEC) were proposed, based on the biological relation to the Stx produced by S. dysenteriae type1 (Calderwood et al. 1996). The second pathway starts in 1983, with the report that a rare E. coli serotype, O157:H7, was the cause of a distinctive clinical entity, named at the time ‘haemorrhagic colitis’ (HC) and characterized by bloody diarrhoea (Riley et al. 1983). In the following years O157:H7 E. coli strains were associated with mild, undifferentiated to severe, bloody diarrhoea, with, in some patients, sequelae such as a haemolytic uraemic syndrome (HUS), characterized by renal failure, and a thrombotic thrombocytopaenic purpura (TTP), possibly with central nervous System (CNS) involvement. As this E. coli serotype had been initially associated with HC, the strains were named ‘enterohaemorrhagic E. coli’ (EHEC) and for many years EHEC remained a clinical definition, synonym of O157:H7 E. coli causing HC. Progressively E. coli strains belonging to other serotypes (026:H11, 0103:H2, 0111:H-, 0145:H-, O157:H-, etc.) were associated with HC, HUS and TTP. Although sometimes reluctantly, the original EHEC definition was widened to include those serotypes. Meanwhile, the properties of the EHEC strains of the O157:H7 and other serotypes were progressively uncovered. Among others, production of the histological attaching/effacing (AE) lesion, very close to the AE lesion caused by enteropathogenic E. coli (EPEC) was recognized. Today the EHEC include all E. coli strains, from humans and animals, producing Stx and AE lesion, or harbouring the genetic information coding for them. However, this definition is not universally accepted as not all of these E. coli cause HC in humans. VTEC and STEC are the names for the strains producing only Stx, like the ED-associated E. coli in piglets. The EHEC and VTEC possess general (serotypes, biotypes and lysotypes) and specific properties (virulence-associated). They are subdivided into different evolutionary lineages: the EHEC-1 lineage comprises the O157:H7 and closely related strains (e.g. O145:H-) that are highly pathogenic in humans (HC, HUS and TTP) and are derived from the O55 EPEC. The EHEC-2 lineage regroups all other EHEC strains belonging to a wide variety of O serogroups (O5, O26, O103, O111, O118, etc.) and of various pathogenicity in humans (diarrhoea, HC and HUS); the VTEC-1 lineage strains belong to the H21 serogroup (O91, O113, etc.) and are pathogens in humans (HUS and TTP). The VTEC-2 lineage corresponds to all other VTEC of low or no pathogenicity (asymptomatic carriage, diarrhoea and rare HUS) in humans. This section will review the specific virulence-associated properties of EHEC and VTEC, i.e. the Stx, the AE lesion and the enterohaemolysins (Ehly). The E. coli Stx toxins consist of two groups: Stx1 are antigenically very close to the Stx toxin of S. dysenteriae type 1 while Stx2 are more distantly related. Variants of Stx1 have been described which differ only slightly in their gene sequences with no consequence on their antigenicity and cell toxicity. The prototype Stx1 is produced by the E. coli strains H19, H30 and EDL933. Several variants of Stx2 have also been described which differ much more from each other in their antigenicity, toxicity and gene sequences. The classification of the Stx2 variants is confusing. It has been proposed that five main biological variants are recognized (Melton-Celsa and O'Brien 1998; Duffy et al. 2001; Thorpe et al. 2002): Stx2 (human strains EDL933 and E32511), Stx2c (human strains E32511 and B2F1), Stx2d [used widely in the literature to describe several other (sub)variants] identical to Stx2c but activatable by components associated with the intestinal mucus (human strain B2F1), Sx2e (porcine strains 412 and S1191) and Stx2f (human strain H.I.8; previously named VTEC strains can produce one Stx toxin or Stx1 and Stx2 (strain Stx2 and Stx2c (strain E32511), two Stx2 (strain The Stx are two the A of is the active and the of is present in five and to the the Stx toxins are by and into the through the The A then into the the and are of a The active have and a from the the of the which are no to with and The is therefore the cells that will all Stx toxins are active on different cell all Stx are highly for Vero the Stx1 and Stx2 only are for HeLa the Stx2c and Stx2d are and the and Stx2f are not Conversely, only and Stx2f are for the Stx2c and Stx2d are and Stx1 and Stx2 are The cell of a Stx on the of specific present on the cell for Stx1 and Stx2 is present on Vero and HeLa for and Stx2f is present on Vero and In vivo In vivo the Stx are produced in the by the EHEC or VTEC, then the intestinal more and the blood The main cells are the endothelial cells of in the and to a gastro-intestinal and and other tissues The are fluid leakage leading to and clinical is in humans as a intestinal by EHEC or VTEC strains in of The Stx cause leading to and possible for HUS is also characterized by and haemolytic et al. 1998; and Although are by EHEC, HUS as they on the endothelial cells of their blood vessels et al. is first of all in piglets suffering leakage of the with of and as main clinical can also be in a few humans intestinal by EHEC or VTEC as of a known as TTP. is also characterized by renal and a et al. 1998; and 1998; Duffy et al. A of have reported that the Stx1 and Stx2 are i.e. cause of fluid in intestinal in and therefore diarrhoea, but this is and can to the animal et al. diarrhoea by EHEC in humans and is to be the consequence of of the AE lesion and not of the production of This is by the of diarrhoea in piglets by ED and in humans by VTEC strains. the the of the diarrhoea in humans, when be the consequence of the of the Stx on the endothelial cells of the vessels present in the intestinal This is not the in as the endothelial cells of their blood vessels Stx et al. and the role of Stx in is In piglets fluid also oedema in the in the leading to the of a the of a in the leading to The A and of the Stx toxins are by two different in one identity the and prototype are in and in at the and Smith 1997; et al. 1998; et al. 1998; Mainil The coding for the different variants are more closely related to the to the The more distantly related to the are the and gene variants each group the are highly The and are present on The and of S. dysenteriae are also on the but not on The of the and to strains by has been in and in vivo 1999; et al. 2003). the Stx toxins are to the by a type The Stx1 toxins are mainly present in the while the Stx2 toxins are more into the at in vitro. The of Stx and but not of the different is at the by high via the and by high The AE lesion is a lesion of the caused by a of strains, named EPEC. of these strains have been known for but only in the early 1980s was the production of this lesion recognized and studied et al. et al. 2003). was that O157:H7 EHEC could produce a very similar lesion and the definition of EHEC was to all E. coli strains producing Stx and AE intestinal and attaching/effacing at the of the of the of the to the of a few with of the The production of AE is the of a very specific and the and the the in This in The first is the of the to the and of the In human this the of several on a pathogenicity on the the of via a The identity of the remains for animal and all EHEC strains. The second in into the cell via a type The type and the are by on the of several cell the type cause of and of the of can differ and EHEC strains belonging to different serotypes and to the The and is an of the to the of the The is a type the the cell is also a for by the type and the the cell this the of the are a the cells and of can be in and the some and EHEC, strains of the cells have been in and in vivo Although the of this is be related to the that the can also as a very similar to the of The of The and for the production of the AE lesion are on a which a type named The comprises to and five and the of pathogenicity of the human enteropathogenic Escherichia coli strain Nataro and Kaper and Duffy et al. The coding for the type and are in is the of the The coding for the type are in the of the In the of the are present the gene coding for the and the gene coding for The of human and animal EHEC and can differ in of and and on the However, the of the on the is et al. et al. has also been described some The of variants of the gene has since the original of the prototype and EHEC et al. 1998; et al. 2000; et al. 2002; Blanco et al. of and have been by and other variants are In variants of the for some and variants differ highly in the of the gene while the of the gene are highly the variants and are identical and the variants and are very closely related. the and variants are but not of human and of O157:H7 EHEC, the other variants are more or less widely in human and animal EHEC and EPEC. the variants have also been described in the and and while the and are more The following and and so et al. 1999; et al. and the other gene variants have not been studied so to The Although the AE lesion is not for the diarrhoea with or The for the diarrhoea is but several have been to in and in vivo These include of and of the major in the of the production of in the and production of The cause of diarrhoea differ strains of different to the the Several types of etc.) are produced by and E. active only on blood cells have been associated with EHEC strains and enterohaemolysins (Ehly). have been described in E. coli, but one is specific of EHEC strains, the or et al. 1998; The to the in of like the The like the is a toxin that into the of the cells and It is by a type but remains to the in to as a consequence of a in the coding for the In vivo the of a with the of HUS in humans, the of the to the of EHEC and VTEC remains unclear. The is by and on a of The gene with the gene coding for the The as all is by a type the of the and is a for the of the a through the with the of the through which is The and to be in the of and can be by the and In that is into the and an like Other are on the coding for a type for a and for a gene in O157:H7 EHEC or gene in The the and is present in all O157:H7 EHEC strains, in a of EHEC strains and in of EHEC strains belonging to other serotypes. The and present on a but not et al. 1998; EHEC and VTEC strains belong to classes on a clinical (i) those highly in humans, but only in EHEC-1 and (ii) those associated with diseases in humans and and (iii) those more associated with disease in humans or The most famous EHEC strains belong to the EHEC-1 lineage and to the O157:H7 to on the O157:H7 of humans with the O157:H7 serotype most as in such as and These are for to and They are rare in and are reported in these other The food are mainly of ruminant such as or O157:H7 EHEC are by to a other ruminants in the gastro-intestinal or and of the The to be the et al. 2003). The faecal for in most animals, but is that some are for of can also originate from other ruminants originate from which have been or by ruminant or by humans. transmission through of and etc.) and of and and or via in or direct animal including and Although the are they have one the foods and food have been or and of the O157:H7 and with other serotypes to a they the of in some for The serogroups O26, O103, and are the most The of for humans, the of in ruminants and the in humans of these are to as include only the O157:H7 with VTEC and have also been but more They not to their in food similar strains can be isolated from ruminant and intestinal and from It is important to that VTEC causing ED in weaned piglets differ by their general and specific properties and that VTEC be as very As VTEC for ED not important concern and as the of EHEC and VTEC described the ruminant animal is 1999; Gyles 2001; this section will on EHEC and VTEC isolated from humans, ruminants and foods are by EHEC which are for HC, HUS and and by VTEC, which are for HUS and only also especially of VTEC strains. EHEC and VTEC belong to an of O serogroups and serotypes. The most of the O157:H7 EHEC and the VTEC serotypes the most famous are and But more other O serogroups in with various serogroups have been described in the literature and are described each et al. serotypes have been isolated from with The of the serotypes with O157:H7 EHEC has been or associated with and other ruminants. direct and indirect contamination also especially an Conversely, the source of human contamination by other serotypes of EHEC and VTEC O103, O111, O113, and is in most many human serotypes have also been isolated from ruminants. The O157:H7 and non-O157 EHEC and VTEC produce Stx1 in similar have been of and The producing Stx2 are more associated with HUS those producing only The variants are mainly and is some of the serotypes and the gene In only very few the variants and have been human strains are EHEC and their belong most to the following all and EHEC the and all EHEC, the of the and In many the of the gene and the of the and are associated with the serogroup while the of the gene and the of the and are associated with the serogroup et al. 1999; et al. O157:H7 EHEC are for the and the of the EHEC and VTEC of other serotypes are for the to the O whose are on a in with two with some strains producing diarrhoea in young of to of and other strains by causing diarrhoea in belong to the EHEC human strains, they belong to an of many of which are also associated with diseases in humans. the O157:H7 EHEC have been associated with diarrhoea in young et al. 1998; Brown et al. 2001; et al. The most important serotypes are and on VTEC strains causing disease in are they have been reported they to other serotypes the of these VTEC serotype have been isolated from human of HUS The of these EHEC are for the gene EHEC the or gene Conversely, VTEC are for the Their gene variants have not been to The of EHEC from are for the gene variants of the and The second most variants are the gene with the and The are in some serogroups but not in Other variants have not or been important to is the identity of the and of and human EHEC belonging to the serotype et al. 1999; et al. Several EHEC and VTEC associated with diarrhoea in young are also for the or for the EHEC but the can from to O serogroups of EHEC and VTEC, in with different have been isolated from more have been described in humans. one type of EHEC and VTEC strains can be isolated not only on the but also from the in to the and to the much from to and and The of are VTEC and only a are O157:H7 The O157:H7 EHEC is in the in as of the The O157:H7 EHEC are identical to the human strains in the in the and in the In the is O157:H7 EHEC isolated in from humans, and et al. et al. Conversely, O157:H7 EHEC on one and in one animal can belong to as by of of human and O157:H7 EHEC to the that not all O157:H7 EHEC are a major and associated with diseases in humans et al. 2003). of E. coli has also been reported et al. The most non-O157 EHEC isolated from belong to the following O O26, O103, O111, and in the of the different serotypes. that they are also similar to human the They are and the gene to the group of As and gene are to the O serogroup can in some if one serogroup half of them are for the production of and for the of the on a VTEC isolated from are also similar to human VTEC associated with disease including HUS by their serotypes etc.) and but can differ to the et al. However, most of them belong to serotypes that have been reported from humans or are of low pathogenicity in humans. The EHEC and VTEC have also been isolated from other ruminants and and from initially from carriers Although the of O157:H7 EHEC in or intestinal of and is in their not differ from the of human and strains. and also a source of contamination for humans. to humans has been reported via of or 1999; Blanco et al. 2001; Brown et al. 2001; Blanco et al. 2003). In and EHEC and VTEC are much more O157:H7 and of faecal more in VTEC are more numerous EHEC and one animal can more one type of and non-O157 EHEC and VTEC belong to human serotypes for EHEC and for or to more serotypes for EHEC and for The of are for the gene the a for the gene the et al. 2001; et al. 2003). Several gene variants have been in a similar to that in human and EHEC and the gene is but in only of The and gene are also to the serogroup et al. 2003). The role of EHEC, and VTEC, in diseases in and is The O157:H7 and EHEC and VTEC are also present in and but on O157:H7 EHEC from has been associated with a of human the they not to be an important source of contamination for as their are different et al. VTEC or E. coli can be isolated from ruminants leading to in In and in et al. 2000; et al. VTEC are more The role of these different strains in the of in the ruminants is foods of animal are the most to be by EHEC and and at the and in The of contamination is to the of intestinal faecal of general O157:H7 and other EHEC strains are in the et al. 1999; and 2001; Brown et al. contamination food can at many the food of of O157:H7 EHEC are a of of certainly by the can be to compare different for and by to be several those with other In and for EHEC and VTEC are not as As a general EHEC and VTEC are more the O157:H7 Conversely, EHEC and VTEC are report of O157:H7 EHEC from and from and are similar in the but can be to in less from and of non-O157 EHEC and VTEC from and are 1 and in the of and and serotypes are identical to those in EHEC and VTEC from humans and from The most gene variants are and et al. but most not type the and gene In other ruminant and the is less is not of EHEC and VTEC are and O157:H7 EHEC are very rare as most to these strains. of non-O157 EHEC and VTEC isolated from and are similar to those in animals, but no of the and have been reported to In and and for non-O157 EHEC and VTEC can be isolated but EHEC are very in most of the strains belong to serotypes and E. coli the the have also been isolated from and can to in The role of ruminants as direct and indirect source of contamination of humans by O157:H7 EHEC is contamination also are for most of the other strains. little is known the of the the epidemiology in and in humans, and the of the EHEC and VTEC strains. strains have been isolated from young and animals, and humans, the of as of contamination for humans. the that and human strains of EHEC and VTEC strains belonging to the serotype and could be on the of their 1999; Brown et al. 2001; et al. 2001; et al. 2003). A first group include strains, while other strains be a group strains of This is to some by the comparison of strains. Their in and in carriage, if any, not in the Stx, in the in the However, in the production of as of the intestinal have been described for different EHEC and VTEC, but their role in the of the is et al. 2001; et al. research not only and of O157:H7 EHEC in humans, ruminants and animals, but also on the non-O157 EHEC and VTEC and to their virulence properties and

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