Escherichia coli is the predominant nonpathogenic facultative flora of the human intestine. Some E. coli strains, however, have developed the ability to cause disease of the gastrointestinal, urinary, or central nervous system in even the most robust human hosts. Diarrheagenic strains of E. coli can be divided into at least six different categories with corresponding distinct pathogenic schemes. Taken together, these organisms probably represent the most common cause of pediatric diarrhea worldwide. Several distinct clinical syndromes accompany infection with diarrheagenic E. coli categories, including traveler’s diarrhea (enterotoxigenic E. coli), hemorrhagic colitis and hemolytic-uremic syndrome (enterohemorrhagic E. coli), persistent diarrhea (enteroaggregative E. coli), and watery diarrhea of infants (enteropathogenic E. coli). This review discusses the current level of understanding of the pathogenesis of the diarrheagenic E. coli strains and describes how their pathogenic schemes underlie the clinical manifestations, diagnostic approach, and epidemiologic investigation of these important pathogens.

Diarrheagenic Escherichia coli

Since their initial recognition 20 years ago, Shiga toxin-producing Escherichia coli (STEC) strains have emerged as an important cause of serious human gastrointestinal disease, which may result in life-threatening complications such as hemolytic-uremic syndrome. Food-borne outbreaks of STEC disease appear to be increasing and, when mass-produced and mass-distributed foods are concerned, can involve large numbers of people. Development of therapeutic and preventative strategies to combat STEC disease requires a thorough understanding of the mechanisms by which STEC organisms colonize the human intestinal tract and cause local and systemic pathological changes. While our knowledge remains incomplete, recent studies have improved our understanding of these processes, particularly the complex interaction between Shiga toxins and host cells, which is central to the pathogenesis of STEC disease. In addition, several putative accessory virulence factors have been identified and partly characterized. The capacity to limit the scale and severity of STEC disease is also dependent upon rapid and sensitive diagnostic procedures for analysis of human samples and suspect vehicles. The increased application of advanced molecular technologies in clinical laboratories has significantly improved our capacity to diagnose STEC infection early in the course of disease and to detect low levels of environmental contamination. This, in turn, has created a potential window of opportunity for future therapeutic intervention.

Pathogenesis and Diagnosis of Shiga Toxin-Producing Escherichia coli Infections

Verocytotoxin (VT)-producing Escherichia coli (VTEC) are a newly recognized group of enteric pathogens which are increasingly being recognized as common causes of diarrhea in some geographic settings. Outbreak studies indicate that most patients with VTEC infection develop mild uncomplicated diarrhea. However, a significant risk of two serious and potentially life-threatening complications, hemorrhagic colitis and the hemolytic uremic syndrome, makes VTEC infection a public health problem of serious concern. The main reservoirs of VTEC appear to be the intestinal tracts of animals, and foods of animal (especially bovine) origin are probably the principal sources for human infection. The term VT refers to a family of subunit exotoxins with high biological activity. Individual VTEC strains elaborate one or both of at least two serologically distinct, bacteriophage-mediated VTs (VT1 and VT2) which are closely related to Shiga toxin and are thus also referred to as Shiga-like toxins. The holotoxins bind to cells, via their B subunits, to a specific receptor which is probably the glycolipid, globotriosyl ceramide (Gb3). Binding is followed by internalization of the A subunit, which, after it is proteolytically nicked and reduced to the A1 fragment, inhibits protein synthesis in mammalian cells by inactivating 60S ribosomal subunits through selective structural modification of 28S ribosomal ribonucleic acid. The mechanism of VTEC diarrhea is still controversial, and the relative roles of locally acting VT and "attaching and effacing adherence" of VTEC to the mucosa have yet to be resolved. There is increasing evidence that hemolytic uremic syndrome and possibly hemorrhagic colitis result from the systemic action of VT on vascular endothelial cells. The role of antitoxic immunity in preventing the systemic complications of VTEC infection is being explored. Antibiotics appear to be contraindicated in the treatment of VTEC infection. The most common VTEC serotype associated with human disease is O157:H7, but over 50 different VT-positive O:H serotypes have now been identified. The best strategies for diagnosing human VTEC infection include testing for the presence of free VT in fecal filtrates and examining fecal cultures for VTEC by means of deoxyribonucleic acid probes that specify genes encoding VT1 and VT2. Both methods are currently confined to specialized laboratories and await commercial development for wider use. In the meantime, most laboratories should continue to screen for the most common human VTEC serotype, O157:H7, using a sorbitol-containing MacConkey medium.

Infection by verocytotoxin-producing Escherichia coli.

Uropathogenic strains of Escherichia coli are characterized by the expression of distinctive bacterial properties, products, or structures referred to as virulence factors because they help the organism overcome host defenses and colonize or invade the urinary tract. Virulence factors of recognized importance in the pathogenesis of urinary tract infection (UTI) include adhesins (P fimbriae, certain other mannose-resistant adhesins, and type 1 fimbriae), the aerobactin system, hemolysin, K capsule, and resistance to serum killing. This review summarizes the virtual explosion of information regarding the epidemiology, biochemistry, mechanisms of action, and genetic basis of these urovirulence factors that has occurred in the past decade and identifies areas in need of further study. Virulence factor expression is more common among certain genetically related groups of E. coli which constitute virulent clones within the larger E. coli population. In general, the more virulence factors a strain expresses, the more severe an infection it is able to cause. Certain virulence factors specifically favor the development of pyelonephritis, others favor cystitis, and others favor asymptomatic bacteriuria. The currently defined virulence factors clearly contribute to the virulence of wild-type strains but are usually insufficient in themselves to transform an avirulent organism into a pathogen, demonstrating that other as-yet-undefined virulence properties await discovery. Virulence factor testing is a useful epidemiological and research tool but as yet has no defined clinical role. Immunological and biochemical anti-virulence factor interventions are effective in animal models of UTI and hold promise for the prevention of UTI in humans. Images

Virulence factors in Escherichia coli urinary tract infection.

There are four major categories of diarrheagenic Escherichia coli: enterotoxigenic (a major cause of travelers' diarrhea and infant diarrhea in less-developed countries), enteroinvasive (a cause of dysentery), enteropathogenic (an important cause of infant diarrhea), and enterohemorrhagic (a cause of hemorrhagic colitis and hemolytic uremic syndrome). Besides manifesting distinct clinical patterns, these categories of E. coli differ in their epidemiology and pathogenesis and in their 0:H serotypes. Common features (albeit distinct for each category) include plasmid-encoded virulence properties, characteristic interactions with intestinal mucosa, and elaboration of various types of enterotoxins or cytotoxins. A less-well-defined fifth category of diarrheagenic E. coli is that of enteroadherent E. coli, so far identifiable only by their pattern of adherence to Hep-2 cells in tissue culture.

Escherichia coli that Cause Diarrhea: Enterotoxigenic, Enteropathogenic, Enteroinvasive, Enterohemorrhagic, and Enteroadherent

Escherichia coli strains isolated from outbreaks of diarrheal disease were tested for the presence of adhesive factors. Fifty-one of these strains belonged to traditional infantile entero-pathogenic serotypes (EPEC) and 17 belonged to other serotypes. None of these strains were enterotoxigenic and none possessed colonization factors CFA/I or CFA/II, which have been described among strains of enterotoxigenicE. coli (ETEC). EnterotoxigenicE. coli strains from patients with diarrhea and strains which were neither EPEC nor ETEC from subjects without diarrhea were also examined. By means of a tissue culture technique using HEp-2 cells, a new adhesive factor was found to occur with greater frequency in EPEC strains. The adhesive factor was found less frequently in the other groups ofE. coli studied. It was distinct from type 1 pili and was not inhibited by the presence ofD-mannose.

An adhesive factor found in strains of Escherichia coli belonging to the traditional infantile enteropathogenic serotypes

Five bacteriophage stocks were prepared after enrichment of a sewage sample using Escherichia coli 02:K1:H4 (strain U9/41). The bacteriophages were tested for their ability to lyse 224 strains of E. coli that had been tested for the presence of the K1 antigen by means of an antiserum-agar diffusion technique, using a meningococcus group B antiserum known to detect the E. coli K1 antigen. The standard test strains for E. coli K antigens 2 to 99 were used as control strains. Of the 101 strains found to possess the K1 antigen using the antiserum-agar technique, 93 were lysed by at least one of the bacteriophages, whereas 8 of the 123 strains apparently lacking K1 were lysed by one or more of the bacteriophages. None of the standard test strains for K antigens 2 to 99 was lysed by any of the bacteriophages. The eight strains thought to lack K1 but that were lysed by bacteriophage were re-examined by immunoelectrophoresis, using meningococcus group B antiserum; five of the eight strains gave a precipitin line corresponding to K1. The use of K1-specific bacteriophages offers an inexpensive and easy method for the identification of the K1 antigen.

Isolation of bacteriophages specific for the K1 polysaccharide antigen of Escherichia coli.

Haemorrhagic colitis and Vero-cytotoxin-producing Escherichia coli in England and Wales.

The first recognized outbreak of haemorrhagic colitis due to Escherichia coli O 157H7 in the United Kingdom affected at least 24 persons living in East Anglia over a 2-week period The illnesses were characterized by severe abdominal pain and bloody diarrhoea of short duration Eleven patients were admitted to hospital and there was one death Patients were mainly adult women who had not eaten out of the home in the 2 weeks before onset Unlike previously reported outbreaks hamburgers were not the vehicle of infection, and a case-control study suggested that handling vegetables, and particularly potatoes, was the important risk factor

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First recognized community outbreak of haemorrhagic colitis due to verotoxin-producing Escherichia coli O 157.H7 in the UK.

Enterotoxigenic Escherichia coli (ETEC) are an important cause of diarrhoea in developing countries. Studies were made, in an endemic area of Bangladesh, of household contacts of patients with diarrhoea associated with E. coli producing heat-stable and heatlabile toxins (ST/LT) or heat-stable toxin (ST) only. It was found that 11% of contacts were infected in the 10-day study period, and that both the rate of infection and the proportion of infected persons with diarrhoea decreased with increasing age, suggesting the development of immunity. ETEC of the same serotype as that of the index patient were found in 9% of water sources used by index households, in a small number of food and drinking water specimens from the index homes, and in faeces from 3 healthy calves. The rate of infection of household members was highest in houses where there was contaminated food or water, which suggests that infection may take place in the home when contaminated water is brought in.

R. J. Gross

Papers

An adhesive factor found in strains of Escherichia coli belonging to the traditional infantile enteropathogenic serotypes

Isolation of bacteriophages specific for the K1 polysaccharide antigen of Escherichia coli.

Haemorrhagic colitis and Vero-cytotoxin-producing Escherichia coli in England and Wales.

First recognized community outbreak of haemorrhagic colitis due to verotoxin-producing Escherichia coli O 157.H7 in the UK.

Enterotoxigenic Escherichia coli diarrhoea: acquired immunity and transmission in an endemic area.