**Abstract**

The term enteropathogenic *Escherichia coli* (EPEC) was first used in 1955 to describe a number of serogroup-defined *E. coli* strains associated with infantile diarrhea. EPEC are now defined as those that produce a characteristic intestinal histopathology known as attaching and effacing (A/E) and do not produce Shiga toxins. EPEC carry the locus for enterocyte effacement (LEE) pathogenicity island, which contains the *eae* gene that encodes an outer membrane protein called intimin. Typical EPEC (tEPEC) carry a virulence plasmid known as the pEAF (EPEC adhesion factor plasmid) which encodes the bundle-forming pilus (BFP) that mediate localized adherence to epithelial cells, whereas atypical EPEC (aEPEC) do not possess this plasmid. Typical EPEC strains have been associated with severe outbreaks of infant diarrhea in developing countries. Atypical EPEC strains have been linked to diarrhea outbreaks at all ages worldwide. Diarrhea due to aEPEC in children is not as severe as that caused by tEPEC.

**Keywords:** *Escherichia coli*, EPEC, diarrhea, children, infantile diarrhea

## **1. History and definition of EPEC**

*Escherichia coli* were first recognized as diarrheal pathogens in 1898, when Lesage demonstrated that serum from diarrhea patients agglutinated strains of *E. coli* isolated from other patients in the same outbreak but not those of control [1]. In 1945, Bray discovered that *E. coli* strains of certain serogroups were the predominant cause of summer diarrhea in infants in the United Kingdom [2]. In 1947, Kauffman published a serotyping scheme based on somatic (O), flagellar (H), and capsular (K) antigens, providing a reliable method of typing diarrheagenic *E. coli* [3].

The term enteropathogenic *Escherichia coli* (EPEC) was introduced in 1955 to describe strains of *E. coli* implicated epidemiologically with infant diarrhea in the 1940s and 1950s [4]. This definition changed as additional serotypes were associated with infantile diarrhea. EPEC were recognized as important causes of infant diarrhea in the 1950s and 1960s in the developed world and subsequently have been shown to be common agents of gastroenteritis in the developing world. The confirmation that EPEC strains were pathogenic came from human volunteer studies carried out by Levine et al. [5].

The definition of EPEC has changed as various mechanisms of pathogenesis have been discovered. During the late 1960s and early 1970s, two other diarrheagenic *E. coli* strains were discovered, strains producing the heat-stable enterotoxin (ST) and the heat-labile enterotoxin (LT) were designated enterotoxigenic *E. coli* (ETEC), and strains demonstrating *Shigella*-like invasiveness were designated enteroinvasive *E. coli* (EIEC). At this time, the original definition of EPEC by Neter [4] has

undergone modification considerably. EPEC were then defined as "diarrheagenic *E. coli* belonging to serogroups epidemiologically incriminated as pathogens but whose pathogenic mechanisms have not been proven to be related either heat-labile (LT) or heat-stable enterotoxins (ST) or to *Shigella*-like invasiveness" [6].

In 1979, the first phenotype characteristic other than serotyping associated with EPEC was the observation of Cravioto et al. [7] that 80% of EPEC strains as defined by serotype could adhere to HEp-2 cells in cell culture, while most non-EPEC strains could not. Later, the adherence pattern of EPEC was described as "localized adherence" (LA), based on the presence of clusters or microcolonies on the surface of HEp-2 cells [8]. Baldini et al. [9] subsequently showed that the ability of EPEC E2348/69 strain (O127:H6) to adhere in a localized adherence pattern was associated with the presence of a 60-MDa plasmid. EPEC strains representing a variety of serotypes were found to possess highly conserved high molecular weight plasmids associated with localized adherence, the so-called EPEC adherence factor (EAF) plasmids [10, 11]. Subsequently, differences in adherence patterns were discerned by Scaletsky et al. [8] and Nataro et al. [12], giving rise to two other categories of diarrheagenic *E. coli* and diffusely adherent *E. coli* and enteroaggregative *E. coli*. Also in the 1980s, a newly recognized clinical syndrome caused by *E. coli* led to the discovery that some diarrheagenic *E. coli* produce a potent cytotoxin known as Shiga toxin (Stx).

In 1983, Moon et al. [13] published electron micrographs of pigs and rabbits infected with EPEC and coined the term "attaching and effacing" (A/E) to describe the loss of microvilli, intimate attachment of the bacteria to the host, and formation of pedestals at the sits of bacteria attachment. In 1987, a number of studies clarified the relationship between LA phenotype and A/E lesion, which confirmed earlier reports that LA is associated with the EAF plasmid, and demonstrated for the first time that A/E is encoded on the chromosome [14].

Originally defined by serotype, EPEC are now defined as those having the ability to cause diarrhea, the ability to produce A/E histopathology on the intestinal epithelium, and the inability to produce Shiga toxins based on pathogenic characteristics [15]. Improvements in techniques allowing a better understanding of the genome and virulence mechanisms among EPEC strains over the years have led to the classification into "typical" and "atypical" subtypes based on the presence or absence of the pEAF plasmid [15].

### **2. Atypical versus typical EPEC**

Most of the typical EPEC strains belong to the traditional EPEC serogroups O55, O86, O111, O114, O119, O127, and O142, and the most common flagellar antigens are H6 and H2 [16, 17]. A less common EPEC type is H34, and a number of typical EPEC strains are nonmotile in conventional testes and classified as H-. Typical EPEC strains belonging to nonclassic serotypes have also been reported [18, 19]. Currently, more than 180 different O serogroups and more than 60 H antigens are recognized. Atypical EPEC belong to a large diversity of classical and nonclassical serotypes [18, 20]. Based on multilocus enzyme electrophoresis analysis of allelic differences among housekeeping genes, typical EPEC strains have been subtyped into two major lineages, previously designated EPEC1 and EPEC2 [16, 17]. EPEC1 includes serotypes O55:H6 and O119:H6, whereas EPEC2 consists of serotypes O111:H2 and O114:H2. Recently, EPEC strains have been demonstrated to cluster in three main lineages, designated EPEC1, EPEC2, and EPEC4, which probably acquired the locus of enterocyte effacement region (LEE) and pEAF independently [21].

**53**

*Enteropathogenic Escherichia coli*

host or in the environment [21].

**3. Epidemiology of EPEC**

**3.1 Incidence**

*DOI: http://dx.doi.org/10.5772/intechopen.82861*

Interestingly, it has been found that 35% of the atypical EPEC strains also belong to the typical EPEC lineages [21]. Thus, it has been hypothesized that at least some atypical EPEC may have originated from typical EPEC strains that lost pEAF in the

The prevalence of EPEC infection varies between epidemiological studies based

For the two last decades, studies conducted worldwide have shown the association of typical EPEC serotypes with diarrhea in children <1 year of age, mainly in poor children of urban centers [24]. This association was particularly strong in infants less than 6 months of age. Between 1977 and 1982, epidemiologic studies in Brazil, Chile, Mexico, and South Africa have shown that 30–40% of infantile diarrhea was caused by typical EPEC serotypes [22]. However, recent studies in these countries have not identified a significant association between typical EPEC and infantile diarrhea. At this time, a change in the epidemiology of EPEC occurred in both developing and developed countries. The proportion of atypical EPEC strains has increased and outnumbered typical EPEC strains, and atypical EPEC strains have also been associated with childhood diarrhea in both developing and developed countries [19, 22, 25]. In Brazil, 92% of EPEC isolates collected from children between 2001 and 2002 were atypical [26], compared to 38% in a 1998–1999 study [27–29]. However, other studies still report typical being more prevalent than atypical EPEC as a cause of diarrhea [30]. Recently, a prospective, population-based case-control study involving seven sites in Africa and Asia showed that typical EPEC was significantly associated with moderate to severe diarrhea in children under 2 years of age in Kenya, whereas atypi-

Typical EPEC transmission follows a fecal-oral process through contaminated surfaces, weaning fluids, and human carriers [32]. EPEC outbreaks among adults, although rare, seem to occur through ingestion of contaminated food and water; however, no specific environmental reservoir has been identified [24]. EPEC outbreaks have been reported to show a seasonal distribution with peaks during the warm months [33]. Humans are the only known reservoir for typical EPEC, with symptomatic and asymptomatic children and asymptomatic adults being the most

In contrast to the tEPEC, many aEPEC strains have been found in diarrheic as well as in healthy animals and from the environment. Interestingly, animal aEPEC serogroups associated with human diarrhea have been identified (e.g., O26, O103, O119, O128, O142, and O157); however, so far a direct transmission from animals to humans has not been confirmed. In addition, foods including raw meats, pasteurized milk, meat samples, vegetables, and water have been also implicated as vehicles

on differences in study populations, age, distributions, and methods used for detection and diagnosis [22]. Also, geographic region and socioeconomic class may contribute to the epidemiology of EPEC-induced diarrheal disease [23]. Adults and older children with typical EPEC infections are rarely reported; this has been attributed to the loss of specific receptors with age or development of immunity [24].

cal EPEC was not associated with this type of diarrhea [31].

of aEPEC to human infections (reviewed in [34, 35]).

**3.2 Transmission and reservoirs**

likely source [24].

Interestingly, it has been found that 35% of the atypical EPEC strains also belong to the typical EPEC lineages [21]. Thus, it has been hypothesized that at least some atypical EPEC may have originated from typical EPEC strains that lost pEAF in the host or in the environment [21].
