Journal of Medical Microbiology (2007), 56, 4–8 DOI 10.1099/jmm.0.

46930-0

Review Enteroaggregative Escherichia coli: epidemiology,

virulence and detection
Andrej Weintraub
Correspondence Karolinska Institute, Department of Laboratory Medicine, Division of Clinical Bacteriology,
Andrej Weintraub Karolinska University Hospital, Huddinge, 14186 Stockholm, Sweden
[email protected]

Enteroaggregative Escherichia coli (EAEC) is a subgroup of diarrhoeagenic E. coli (DEC) that

during the past decade has received increasing attention as a cause of watery diarrhoea, which is
often persistent. EAEC have been isolated from children and adults worldwide. As well as sporadic
cases, outbreaks of EAEC-caused diarrhoea have been described. The definition of EAEC is the
ability of the micro-organism to adhere to epithelial cells such as HEp-2 in a very characteristic
‘stacked-brick’ pattern. Although many studies searching for specific virulence factor(s) unique for
this category of DEC have been published it is still unknown why the EAEC cause persistent
diarrhoea. In addition, the aggregative property of EAEC causes a lot of problems in serotyping due
to the cells auto-agglutinating. The gold standard for identification of EAEC includes isolation of the
agent and an adherence assay using tissue culture, viz. HEp-2 cells. This assay is in most cases
reliable; however, emergence of ‘atypical’ EAEC has been described in several publications. In
addition, the HEp-2 assay is time consuming, demands a tissue culture lab and trained staff. Several
molecular biological assays have been described, however, none show 100 % specificity.

Introduction mechanisms. The EIEC, EHEC and ETEC are defined as

Escherichia coli is the type species of the genus Escherichia E. coli strains possessing specific virulence attributes,
that contains mostly motile Gram-negative bacilli that fall including different toxins, invasion plasmid and coloniza-
within the family Enterobacteriaceae. It is the predominant tion factors. Almost half a century ago, Ewing et al. (1963)
facultative anaerobe of the human colonic flora. The determined that certain serotypes of E. coli were associated
organism typically colonizes the infant gastrointestinal with outbreaks of diarrhoea. Strains belonging to these
tract within hours of life, and thereafter E. coli and the serotypes were referred to as EPEC. In 1979, Cravioto and
host derive mutual benefit for decades (Kaper et al., 2004). colleagues described an in vitro assay based on the adhesion
However, there are several highly adapted E. coli clones that of the bacteria to HEp-2 cells showing that EPEC bind to the
have acquired specific virulence factors, which increase their cells in a localized pattern (Cravioto et al., 1979). A few years
ability to adapt to new niches and allow them to cause a later it was shown that adherent non-EPEC strains were
broad spectrum of diseases. Three general clinical syn- associated with diarrhoea. These strains were called
dromes can result from infection with pathogenic E. coli ‘enteroadherent E. coli’ (Cravioto et al., 1991; Mathewson
strains: enteric/diarrhoeal disease, urinary tract infection et al., 1985, 1987). At the same time, Nataro et al. (1987)
and sepsis/meningitis (Nataro & Kaper, 1998). As long as recognized two different phenotypes among the enteroad-
these bacteria do not acquire genetic elements encoding herent strains, i.e. diffuse and aggregative. The finding of
virulence factors, they remain benign commensals. Strains Nataro was the first description of EAEC. The aggregative
that acquire ‘foreign’ DNA encoding enterotoxins, adhesins adherence is characterized by a ‘stacked-brick’ formation of
or invasion factors become virulent and can cause either a bacterial cells attached to the HEp-2 cells (Nataro & Kaper,
plain, watery diarrhoea or inflammatory dysentery. 1998; Nataro et al., 1998). The basic strategy of EAEC seems
to comprise colonization of the intestinal mucosa, probably
predominantly that of the colon, followed by secretion of
Enteroaggregative E. coli enterotoxins and cytotoxins (Nataro et al., 1998). Studies on
Among the E. coli causing intestinal diseases, there are six human intestinal specimens indicate that EAEC induces
well-described categories: enteroaggregative E. coli (EAEC), mild, but significant, mucosal damage (Hicks et al., 1996).
diffusely adherent E. coli (DAEC), enteroinvasive E. coli EAEC strains characteristically enhance mucus secretion
(EIEC), enteropathogenic E. coli (EPEC), enterohaemor- from the mucosa, with trapping of the bacteria in a
rhagic E. coli (EHEC) and enterotoxigenic E. coli (ETEC) bacterium-mucus biofilm (Nataro & Kaper, 1998). Two
(Nataro & Kaper, 1998). These categories have virulence further observations support a role of mucus in EAEC
attributes that help bacteria to cause diseases by different pathogenesis: EAEC bound avidly in the rabbit in vitro

4 46930 G 2007 SGM Printed in Great Britain

 EAEC: epidemiology, virulence and detection

model (Wanke et al., 1990) and volunteers fed EAEC strains group was 39 % (Vu Nguyen et al., 2006). Many of the
excrete mucoid stools (Nataro et al., 1995). The formation epidemiological surveys that identified EAEC as a diarrhoeal
of a heavy biofilm may be related to the diarrhoeagenicity of pathogen were done in developing countries. However,
the organisms and, perhaps, to its ability to cause persistent EAEC has been found to be associated with diarrhoea in
colonization and diarrhoea. In addition to forming a developed countries as well.
mucous biofilm, many EAEC strains induce cytotoxic effects
on the intestinal mucosa. In animal models infected with
EAEC in rabbit and rat ileal loops, light microscopy showed Developed countries
some destructive lesions (Vial et al., 1988). EAEC also In a Scandinavian case–control study the prevalence and the
induced shortening of the villi, haemorrhagic necrosis of the association of EAEC with diarrhoea was greater than for
villous tips, and a mild inflammatory response with oedema EPEC (Bhatnagar et al., 1993). Another study conducted in
and mononuclear infiltration of the submucosa. Both light
east London showed that EAEC could be recovered from
and electron microscopy showed adherent bacteria without
children with acute and persistent diarrhoea (Chan et al.,
the attaching and effacing lesion, which is characteristic of
1994). A clear association of EAEC with diarrhoea in
EPEC. The clinical features of EAEC diarrhoea are
children in Germany was shown by Huppertz et al. (1997)
increasingly well defined in outbreaks, sporadic cases and
who recovered EAEC from 16 (2 %) of 798 children with
the volunteer model. Typical illness is characterized by
diarrhoea but none from 580 healthy controls. Other
watery, mucoid, secretory diarrhoea with low-grade fever
and little to no vomiting (Bhan et al., 1989b; Paul et al., European studies in children (Knutton et al., 2001; Presterl
1994). However, up to one third of patients with EAEC et al., 1999) also indicate that EAEC may be a leading cause
diarrhoea had grossly bloody stools (Cravioto et al., 1991). of diarrhoeal disease in developed as well as developing
countries. In a Serbian neonatal ward an outbreak of EAEC
Epidemiology diarrhoea was described by Cobeljic et al. (1996) where 19
babies were affected and 3 of these patients got diarrhoea.
Developing countries One EAEC strain resistant to multiple antibiotics was
A growing number of studies have supported the association implicated. In the largest reported outbreak so far, 2697
of EAEC with diarrhoea in developing countries, most (40.6 %) Japanese children who ate infected school lunches
prominently in association with persistent diarrhoea (Bhan had severe diarrhoea and EAEC was found in 10 % of cases
et al., 1989a, b, c; Fang et al., 1995; Lima et al., 1992). Several (Itoh et al., 1997). Several other outbreaks both in children
studies in children with diarrhoea have shown a significant and in adults have been described in the UK (Smith et al.,
difference in the prevalence of EAEC compared to the 1997; Spencer et al., 1999), India (Pai et al., 1997) and France
controls (Bhatnagar et al., 1993; Bouzari et al., 1994; (Boudailliez et al., 1997; Morabito et al., 1998).
Cravioto et al., 1991; Gonzalez et al., 1997; Nataro et al.,
1987). EAEC and persistent diarrhoea syndrome have been In a 1 year prospective Swedish study on enteropathogens in
consistently associated (Fang et al., 1995; Lima et al., 1992; adult patients with diarrhoea and healthy control subjects,
Wanke et al., 1991). The increasing number of such reports 105 of 760 patients with diarrhoea were positive for DEC.
and the rising proportion of diarrhoeal cases in which EAEC EAEC was present in 16 cases and was the second most
are implicated suggest that EAEC are important emerging common isolate among DEC surpassed only by ETEC
agents of paediatric diarrhoea. (Svenungsson et al., 2000). Other studies have shown that
this pathogen is an important cause of travellers’ diarrhoea
During the initial years after the discovery of EAEC there (Adachi et al., 2001; Gascón et al., 1998; Schultsz et al.,
were a lot of doubts about the pathogenicity of this category
2000). However, documented reports are less common
of diarrhoeagenic E. coli (DEC) (Echeverria et al., 1992;
because EAEC is not sought in many studies. Travellers to all
Gomes et al., 1989). However, Nataro et al. (1995) showed
developing countries are at risk and if EAEC were sought in
that a reference strain of EAEC could cause diarrhoea in a
all laboratories, infection by this pathogen could explain
volunteer study. In addition, a number of outbreaks have
over 25 % of cases for which no pathogen is recovered
proven that at least some EAEC strains cause diarrhoea in
(Adachi et al., 2001).
humans. Furthermore, many case–control and cohort
surveys of the past 15 years strongly suggest that EAEC is
an important cause of diarrhoea in people of all ages in
developing and industrialized countries. In a recent study Immunocompromised
from Vietnam by Vu Nguyen et al. (2006) it was shown that Diarrhoea is an important cause of morbidity in the
EAEC is more frequently associated with diarrhoea in immunocompromised. A wide range of pathogens is
children less than 2 years of age. In this study, 587 children implicated in AIDS-associated diarrhoea, and in many
of less than 5 years of age with diarrhoea and 249 age- cases a causative agent is not found. Case reports from
matched healthy controls were examined for, among other Mayer & Wanke (1995) described that EAEC could be
pathogens, EAEC. Of all identified EAEC strains in the recovered from diarrhoeal stools from AIDS patients. There
diarrhoeal group, 87 % were isolated from children less than have been other reports after epidemiological surveillance
2 years of age. The corresponding figure for the control among HIV-positive patients (Mayer & Wanke, 1995).

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A. Weintraub

Virulence factors in the literature as non-typable or as O-rough. It is also well

established that the EAEC group is highly heterogeneous.
In order to cause diarrhoeal disease, EAEC adheres to
Huppertz et al. (1997) analysed EAEC from German children
intestinal mucosa, forms a mucoid biofilm and induces toxic
and found that of 14 typable isolates all belonged to different
effects on the intestinal mucosa that result in diarrhoea. The
serotypes. In another study in the UK, 97 EAEC strains were
exact mechanism of pathogenesis is not fully understood;
serotyped to 40 different O-types. However, the remaining
however, adhesins, toxins and several other factors have
121 EAEC isolates were non-typable (Food Standards Agency,
been implicated. Certain strains carry a high molecular
2000). In a study by Jenkins et al. (2006a), 93 out of 143 EAEC
weight plasmid associated with the aggregative adherence
strains could be serotyped and belonged to as many as 47
(Law et al., 1998; Vial et al., 1988), on which a number of
different serotypes. This shows that serotyping, although
virulence genes are located. These are (i) heat stable toxin-1
useful in the characterization of other DEC, is of little value in
(EAST-1) (Savarino et al., 1991), (ii) aggregative adherence
the diagnosis of EAEC. As mentioned earlier, the HEp-2
fimbriae I and II (AAF/I and AAF/II) (Nataro et al., 1992;
adherence test is the gold standard for the identification of
Rich et al., 1999), as well as the AAF/III (Bernier et al., 2002).
EAEC. This test requires specialized facilities and can
Also located on the plasmid are (i) transcriptional activator
therefore only be conducted in reference laboratories, and
gene (Nataro et al., 1994, 1998), (ii) anti-aggregation
strict adherence to protocol is required (Haider et al., 1992;
protein gene (Sheikh et al., 2002), and (iii) anti-aggregation
Vial et al., 1990). Several attempts have been made to develop
protein transporter gene (Baudry et al., 1990). In
a molecular biological assay for the identification of EAEC. In
addition, the plasmid-encoded toxin (Eslava et al., 1998)
1990, Baudry and colleagues developed a DNA probe,
and a cryptic ORF known as shf (Czeczulin et al., 1999) have
CVD432, that was found to be 89 % sensitive and 99 %
been described. Other virulence factors that are believed to
specific for EAEC (Baudry et al., 1990). Based on this probe, a
be associated with EAEC are 18 and 30 kDa outer-
PCR assay was developed by Schmidt et al. in 1995. This assay
membrane adhesins (Chart et al., 1997; Debroy et al.,
has been widely used since then. In search for additional
1995; Grover et al., 2001). In addition, different pathogeni-
virulence factors, several other assays have been described,
city islands have been identified within the EAEC group,
none of which with has as high sensitivity and specificity as
including Shigella she pathogenicity island, containing
the one described in 1995. The problems in identification of
enterotoxin and mucinase genes (Henderson et al., 1999),
EAEC have been clearly highlighted very recently (Jenkins
and Yersinia high-pathogenicity island, containing the
et al., 2006b). The authors set up a multiplex PCR targeting
yersiniabactin siderophore gene (Schubert et al., 1998).
three different genes: (i) the anti-aggregation protein
Strains that carry the high molecular weight plasmid
transporter gene described by Baudry et al. (1990), (ii) the
represent an important subgroup (Cerna et al., 2003; Elias
EAST gene (Savarino et al., 1991) and (iii) a chromosomal
et al., 2002) and may be regarded as ‘typical EAEC’.
gene present in the pheU pathogenicity island designated
However, EAEC is a heterogeneous group of E. coli
aggR-activated island (Jenkins et al., 2006b). The authors used
(Czeczulin et al., 1999) and certain strains, although
this multiplex PCR to identify EAEC from patients in the
adherent to the HEp-2 cells in the stacked-brick mode,
community suffering from diarrhoea. They found that twice
lack the high molecular weight plasmid and can be called
as many isolates were positive against at least one of the
‘atypical EAEC’ (Cobeljic et al., 1996; Elias et al., 2002;
primers as compared to the HEp-2 adherence assay alone.
Gioppo et al., 2000; Itoh et al., 1997).

Identification – serotyping and molecular Conclusion

biology
The HEp-2-adherence assay and/or the CVD432 standard
However, none of the above-described gene(s) is conserved probe represent the best means at present for detecting EAEC.
among all of the EAEC and many are not unique to this However, it is clear that more sensitive, specific and practical
category of DEC. Recently, Jenkins et al. (2006a) used several methods are needed in order to improve the diagnosis of
different probes to characterize EAEC strains. The results infected cases with EAEC and to understand the disease.
show that the majority of the HEp-2 positive strains were also
positive for the anti-aggregation protein transporter gene
described by Baudry et al. (1990) against which Schmidt and
colleagues developed a PCR assay in 1995 (Schmidt et al., Note from the editor-in-chief
1995). Overall, 143 EAEC strains were analysed and 128 A review on EAEC by Huang and colleagues was published
(90 %) were positive for the anti-aggregation protein in the Journal of Medical Microbiology October 2006 issue
transporter gene (Jenkins et al., 2006a). However, 10 % of (Huang et al., 2006) that concentrated on the epidemiology
the strains verified by HEp-2 assay were negative in the PCR and pathogenic mechanisms of the bacterium. More
assay. This makes it difficult to provide a genotypic definition recently a paper by Jenkins and colleagues (Jenkins et al.,
for EAEC and to design specific molecular biological assays 2006b) has been published drawing attention to the
for the detection of this pathotype. In addition, serotyping of difficulties in diagnosing EAEC infection by molecular
EAEC is a problem. Due to their aggregative phenotype, methods. This mini review by Andrej Weintraub discusses
many of the strains auto-agglutinate and are often described the problem further.

6 Journal of Medical Microbiology 56

 EAEC: epidemiology, virulence and detection

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