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Review |
1 Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, 535EE, Houston, TX 77030, USA
2 University of Texas at Houston School of Public Health, 1200 Herman Pressler - E50, Houston, TX 77030, USA
3 University of Texas at Houston Medical School, 6431 Fannin Street, Houston, TX 77030, USA
4 St. Luke's Episcopal Hospital, 6720 Bertner Avenue, MC 1-164, Houston, TX 77030, USA
5 New Jersey Veterans Affairs Medical Center, 385 Tremont Avenue, East Orange, NJ 07018-1023, USA
Correspondence
David B. Huang
dhuang82{at}hotmail.com
Abbreviations: ABC, ATP-binding cassette; AAF, aggregative adherence fimbriae; CI, confidence interval; DAEC, diffusely adherent E. coli; EAEC, enteroaggregative E. coli; EHEC, enterohaemorrhagic E. coli; EPEC, enteropathogenic E. coli; ETEC, enterotoxigenic E. coli; IL, interleukin; OMP, outer-membrane protein; OR, odds ratio.
General considerations
Diarrhoeagenic Escherichia coli is categorized into the following six pathotypes: enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enterohaemorrhagic E. coli (EHEC), enteroinvasive E. coli (EIEC), diffusely adherent E. coli (DAEC), and enteroaggregative E. coli (EAEC). Other diarrhoeagenic E. coli pathotypes have been proposed, such as cell detaching E. coli (CDEC); however, their significance remains uncertain (Abduch-Fabrega et al., 2002; Clarke, 2001). Each of the pathotypes has distinguishing characteristics related to epidemiology, pathogenesis, clinical manifestations and treatment. EAEC is the most recently identified and described diarrhoeagenic E. coli. This bacterium was described in 1987, and identified in a child from Chile with persistent diarrhoea (Nataro, 2005).
EAEC has caused large diarrhoeal outbreaks in Europe, the UK, Switzerland and Japan. EAEC is also a common bacterial cause of diarrhoea among travellers to developing countries, and among children and HIV-infected persons residing in developing and developed regions of the world (Ruttler et al., 2002; Nataro et al., 2006). The virulence of EAEC strain 042 has been established in volunteers, who develop diarrhoea following an experimental challenge with an inoculum of 1010 c.f.u. (Nataro et al., 1995). A high inoculum required for disease development suggests a food or water vehicle as the likely mode of disease transmission for EAEC strains. A study of Mexican tabletop sauces identified 44 % of sauces from Guadalajara, Mexico, to contain viable EAEC, compared to 0 % of sauces in restaurants in Houston, TX (Adachi et al., 2002b).
EAEC is increasingly recognized as an emerging enteric pathogen. EAEC is a cause of persistent diarrhoea and malnutrition in children and HIV-infected persons living in developed countries, is the second most common cause of travellers' diarrhoea (ETEC is the most common cause), and is a common cause of acute diarrhoeal illness in children and adults (4.5 %) presenting to emergency departments and inpatient units in the USA (Cohen et al., 2005; Nataro et al., 2006). EAEC is also considered a potential bioterrorism agent (National Institutes of Health category B) (Huang & DuPont, 2004; Huang et al., 2004b). The objective of this review is to provide an update on this increasingly recognized emerging enteric pathogen.
Epidemiology
Numerous epidemiological studies of EAEC have been conducted. In a meta-analysis of published studies, EAEC was a cause of acute diarrhoeal illness in a median of 15 % of children living in developing countries and 4 % of children living in industrialized countries (Huang et al., 2006). These and other studies have examined the role of EAEC as a cause of diarrhoeal illness among other populations, in different regions of the world (Sanders et al., 2004; Sarantuya et al., 2004; Cohen et al., 2005). The populations best studied include children, adults and HIV-infected persons, living in developing and developed regions, and international travellers to developing countries. Many of these epidemiological studies conflict with regard to the pathogenicity of EAEC strains (Vernacchio et al., 2006), and many of these studies were not able to determine the importance of EAEC as a cause of diarrhoeal illness.
The data that support the virulence of EAEC come from a volunteer challenge study of EAEC prototype strain 042; outbreaks reported in Europe, the UK, Switzerland and Japan; large case-series and cohort studies of children, adults and HIV-infected persons living in developing and developed countries; and cases among international travellers to developing countries. In a volunteer challenge study, four groups of five volunteers were fed with one of four EAEC strains (042, 17-2, 34b and JM 221), each at a dose of 1010 c.f.u. (Nataro et al., 1995). Strain 042 caused diarrhoea in one group (three of five adults), whereas the other three strains failed to cause diarrhoea. These results support case-control and cohort-study findings of heterogeneity of EAEC in virulence. Four outbreaks of gastroenteritis due to EAEC occurred in the UK in 1994, occurring at different locations and at different times, and involving 19, 10, 51 and 53 persons, respectively. These illnesses were characterized by vomiting, diarrhoea and low-grade fever (Smith et al., 1997). In 1993, a massive outbreak of diarrhoea due to EAEC serotype O : H10 occurred in Japan. A total of 2697 children from 16 schools developed symptoms of abdominal pain, nausea and diarrhoea after presumably consuming contaminated school lunches (Itoh et al., 1997).
Several large population-based case-series of persons infected with EAEC have been described (Zamboni et al., 2004; Dulguer et al., 2003; Kang et al., 1995; Bhatnagar et al., 1993; Wilson et al., 2001; Knutton et al., 2001; Huppertz et al., 1997; Svenungsson et al., 2000). Table 1
shows pooled odds ratios (ORs) and confidence intervals (CIs) from a meta-analysis of epidemiologic studies of EAEC infections, identified by the HEp-2 cell-adherence assay, by population and region of the world (Huang et al., 2006). The OR represents the ratio of patients with diarrhoea from whom EAEC was isolated compared with those with asymptomatic EAEC infection. From the studies, EAEC was associated with acute diarrhoeal illness among children residing in developing and industrialized regions, HIV-infected adults residing in developing regions, adults residing in developing regions, and international travellers to developing regions. Limited studies have examined the role of EAEC in acute diarrhoeal illness among HIV-infected adults and non-HIV-infected adults residing in industrialized regions. Additional studies that are able to examine the role of EAEC in acute diarrhoea are needed.
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Like ETEC, EAEC is transmitted by the faecal–oral route. Risk factors for EAEC include travel to developing countries, ingestion of contaminated food and water, poor hygiene, host susceptibility, and possibly immunosuppression (HIV infection) (Huang & DuPont, 2004; Huang et al., 2004b). Although EAEC has been identified as a cause of acute and chronic diarrhoea, it is unclear if HIV-infected persons are more likely to develop symptomatic EAEC infection in comparison to non-HIV-infected persons. It is also uncertain if EAEC represents an opportunistic infection (Gassama-Sow et al., 2004).
Pathogenesis
The pathogenesis of EAEC is complex, and EAEC strains are very heterogeneous (Elias et al., 2002). Human and animal studies indicate that EAEC is able to bind to jejunal, ileal and colonic epithelium. Electron microscopy of infected small- and large-intestinal mucosa, from children between 3 and 190 months, cultured with several different EAEC strains, reveals bacteria in a thick mucus layer above the intact enterocyte brush border (Hicks et al., 1996). In the colon, EAEC elicits inflammatory mediators and produces cytotoxic effects such as microvillus vesiculation, enlarged crypt openings, and increased epithelial cell extrusion (Harrington et al., 2005). Numerous putative virulence factors, a yersiniabactin system, a complex carbohydrate-specific lectin (Basu et al., 2004), enterotoxins and cytotoxins have been identified, but the clinical implication of these factors remains unclear (Table 2) (Jenkins et al., 2005; Jiang et al., 2002; Moon et al., 2005; Hu et al., 2005). The best-studied virulence factor is AggR, the master regulator of EAEC virulence, which controls expression of adherence factors, a dispersin protein, and a large cluster of genes encoded on the EAEC chromosome (Nataro, 2005). EAEC pathogenesis involves three stages: (1) adherence to the intestinal mucosa by aggregative adherence fimbriae (AAF) and adherence factors; (2) production of mucus by bacteria and the host cell forming a biofilm on the surface of the enterocytes; and (3) release of toxins and elicitation of an inflammatory response, mucosal toxicity and intestinal secretion (Nataro, 2005; Huang et al., 2004a; Harrington et al., 2005).
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AggR regulates the expression of a secreted low-molecular-weight protein known as dispersin (aap) (Sheikh et al., 2002). Aap lies immediately upstream of aggR in EAEC strain 042. Dispersin is a 10.2 kDa protein that has been identified in 80 % of EAEC isolates from one laboratory (Sheikh et al., 2002). This protein is exported by an ATP-binding cassette (ABC) transporter complex which is encoded by a genetic locus on the EAEC virulence plasmid pAA2 (Nishi et al., 2003). The locus consists of a cluster of five genes (designated aat-PABCD), including homologues of an inner-membrane permease (AatP), an ABC protein (AatC) and an OMP TolC (AatA). AatA localizes to the outer membrane independently of its ABC partner. Dispersin appears to require the Aat complex for outer-membrane translocation, but not for secretion across the inner membrane. In a similar manner to the dispersin gene (aap), transcription of the aat cluster is dependent on AggR, a regulator of a package of virulence genes in EAEC (Jenkins et al., 2005). Dispersin is responsible for mediating dispersal of EAEC across the intestinal mucosa to allow for efficient adherence and aggregation. This protein neutralizes the negatively charged LPS of the EAEC surface, allowing the positively charged AAF to splay out from the bacterium. In a volunteer challenge study, dispersin has been shown to be highly immunogenic, suggesting that it is a potential vaccine candidate (Nataro et al., 1995). Undoubtedly, other potential AAF and adherence factors exist, and they are currently being investigated.
The second stage of EAEC pathogenesis involves production of a mucus layer by the bacteria and the intestinal mucosa. Animal and in vitro culture studies show that EAEC survives within the mucus layer, explaining why individuals infected with EAEC, especially children in developing countries with pre-existent malnutrion, may develop mucoid stools, malnutrition, and persistent colonization with prolonged diarrhoea. One study has identified biofilm production in 48 of 62 (77 %) EAEC strains from Japanese children with diarrhoea, using a quantitative biofilm assay, suggesting that this assay may be a useful and convenient screening tool for EAEC (Wakimoto et al., 2004). Transposon mutagenesis studies suggest that biofilm production by EAEC strain 042 is dependent on two genes. Fis is a chromosomal gene encoding a DNA-binding protein involved in growth-phase-dependent regulation, and yafK encodes a secreted 28 kDa protein (Sheikh et al., 2001). Both genes are mediated by AAF and likely reflect its interaction with the intestinal mucosa. Molecular epidemiologic studies are ongoing to determine the clinical impact of infection with EAEC strains that produce biofilm, and to investigate the genetic markers that identify biofilm-producing EAEC.
The third stage of EAEC pathogenesis involves release of EAEC toxins, and elicitation of an inflammatory response, mucosal toxicity and intestinal secretion. Numerous EAEC toxins have been described. Both animal and human studies show that EAEC toxins are destructive to the tips and sides of intestinal villi and enterocytes. Several toxins are part of this process. The three toxins best studied are plasmid-encoded toxin (Pet) (Navarro-Garcia et al., 2001), EAEC heat-stable enterotoxin (EAST1) (Menard & Dubreuil, 2002), and Shigella enterotoxin 1 (ShET1) (Behrens et al., 2002). Pet is a cytopathic serine protease autotransporter that functions as an enterotoxin and a cytotoxin (Dutta et al., 2002). Intracellular expression of Pet is accompanied by cleavage of spectrin within the cytoskeleton of intestinal microvilli. In vitro studies show that purified toxin induces cell elongation and rounding, followed by exfoliation of cells from the substratum. These effects are accompanied by loss of actin stress fibres and electrophysiologic changes (Sui et al., 2003). EAST1 is encoded by astA and is a heat-stable protein similar to the heat-stable toxin of ETEC. EAST1 was originally detected in EAEC strains. However, EAST1 has subsequently been identified in ETEC, EHEC, EPEC and DAEC.
The host inflammatory response to EAEC infection is dependent on the host innate immune system and the EAEC strain. The role of putative virulence genes and clinical outcomes is unclear. EAEC carrying ‘virulence’ genes are not always associated with disease; however, virulence factors are associated with increased levels of faecal cytokines and inflammatory markers, such as interleukin (IL)-1ra, IL-1ß, IL-8, interferon (INF)-
, lactoferrin, faecal leukocytes, and occult blood (Jiang et al., 2002; Huang et al., 2004b). IL-8 is an important pro-inflammatory chemokine involved in EAEC pathogenesis. IL-8 is responsible for recruiting neutrophils to the epithelial mucosa without mucosal injury, and facilitates intestinal fluid secretion (Kucharzik et al., 2005; Sansonetti et al., 1999; Madara et al., 1993). Travellers to Mexico who developed symptomatic illness due to EAEC infection excreted high concentrations of faecal IL-8 compared to travellers who did not develop diarrhoea due to EAEC infection (Jiang et al., 2003). In addition to IL-8, intestinal epithelial cells infected with EAEC 042, the prototype strain, have been shown to upregulate the following genes: IL-6, tumour necrosis factor (TNF)-
, growth-related gene product (GRO)-, GRO-, intercellular adhesion molecule (ICAM)-1, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-1. These cellular responses are primarily mediated by flagellin (fliC), a major bacterial surface protein of EAEC (Harrington et al., 2005). Flagellin causes IL-8 release from several epithelial cell lines by binding to Toll-like receptor 5 (TLR5). TLR5 signals through P38 mitogen-activating protein kinase (MAPK) and nuclear factor kappa B (NF-
B) to induce transcription of pro-inflammatory cytokines from epithelial and monocytic cells (Khan et al., 2004). MAPK is a member of a family of stress-related kinases that influences a diverse range of cellular functions, including host inflammatory responses to microbial products (Khan et al., 2004). It is clear that multiple factors contribute to EAEC-induced inflammation, and further characterization of the nature of EAEC pro-inflammatory factors will greatly advance the understanding of this emerging pathogen.
Clinical manifestations of EAEC infection
The clinical symptoms of EAEC infection vary from one study to another (Table 3). Although not all EAEC infections result in symptomatic illness (Adachi et al., 2002a), most studies suggest that EAEC infection results in gastrointestinal disease. The most commonly reported symptoms are watery diarrhoea with or without blood and mucus, abdominal pain, nausea, vomiting, and low-grade fever. EAEC can cause both an acute and a chronic (>14 days) diarrhoeal illness. Malnourished hosts, especially children living in developing countries, may be unable to repair mucosal damage and thus may become prone to persistent or chronic diarrhoea. The incubation period of EAEC diarrhoeal illness ranges from 8 to 18 h. The myriad variations of clinical symptoms of EAEC infection are due to factors such as host genetic susceptibility, host immune response, heterogeneity of virulence among EAEC strains, and the amount of bacteria ingested by the infected host.
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Diagnosis
The gold standard for identifying EAEC is the HEp-2 cell-adherence assay (Nataro & Kaper, 1998). This assay identifies EAEC by its ‘stacked brick’ aggregating phenotype (Fig. 1). Variations in the assay have been described. A formalin-fixed HEp-2 cell-adherence assay is reported to be sensitive (98 %) and specific (100 %) compared to the traditional assay, while reducing the risk of contamination (Miqdady et al., 2002). It remains to be determined if this assay will improve the efficiency of EAEC identification and be routinely used in diagnostic laboratories. The HEp-2 cell-adherence assay is currently performed only in research settings, and is labour intensive (Huang et al., 2004b). A clump formation test has also been described to be useful in the identification of EAEC (Iwanaga et al., 2002).
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) (Bouzari et al., 2005; Ruiz-Blazquez et al., 2005). A DNA probe from the pAA plasmid of EAEC is specific for EAEC strains, but has variable sensitivity (Scaletsky et al., 2002). A PCR, a multiplex PCR, and a real-time PCR assay to detect EAEC virulence genes and a plasmid region corresponding to the DNA probe, are also available (Amar et al., 2004). A problem with using DNA probes and PCR assays to identify EAEC is that EAEC strains are very heterogeneous, and this may account for the varying sensitivity of these techniques (Sarantuya et al., 2004).
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Two clinical trials have been conducted evaluating treatment of EAEC diarrhoea in travellers (Table 5). The first trial evaluated the clinical response of travellers with EAEC diarrhoea to ciprofloxacin (500 mg twice a day for 3 days) (Glandt et al., 1999), and the second trial evaluated the clinical response to rifaximin (200 and 400 mg twice a day for 3 days), a poorly absorbed antimicrobial agent (Infante et al., 2004). In the first trial, 29 of 64 (45 %) US travellers to Jamaica and Mexico developed diarrhoea due to EAEC. Sixteen of the patients were treated with ciprofloxacin and 13 with placebo. The patients treated with ciprofloxacin had a significant reduction in the duration of post-treatment diarrhoea (35 versus 56 h), and a non-significant reduction in the mean number of unformed stools passed during the 72 h after enrolment compared to patients who received placebo (six episodes versus eight episodes). The second trial was multicentred, and included 43 of 137 (32 %) US travellers to Guatemala, Kenya and Mexico who developed diarrhoea due to EAEC. Thirty of the patients were treated with rifaximin and 13 with placebo. The patients treated with rifaximin had a significant reduction in the duration of post-treatment diarrhoea compared to placebo (22 versus 72 h).
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Financial disclosures
None of the authors has any financial disclosures or conflicts of interest to report.
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