Pathogenic E. coli

T. J. Clark

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Pathogenic E. coli

E.coli.combo picture

Left: Escherichia coli cells. Right: E.coli colonies on EMB Agar

Pathogenic E. coli

The GI tract of most warm-blooded animals is colonized by E. coli within a few hours or days after birth by the bacterium ingested in foods or water or directly from other individuals. The human bowel is usually colonized within 40 hours of birth. E. coli can adhere to the mucus overlying the large intestine. Once established, an E. coli strain may persist for months or years. Resident strains shift over a long period (weeks to months), and more rapidly after enteric infection or antimicrobial chemotherapy that perturbs the normal flora. The basis for these shifts and the ecology of Escherichia coli in the intestine of humans are poorly understood despite the vast amount of information on almost every other aspect of the organism's existence. In fact, the entire DNA base sequence of the E. coli genome is known.

E. coli is the head of the large bacterial family, Enterobacteriaceae, the enteric bacteria, which are faculatively anaerobic Gram-negative rods that live in the intestinal tracts of animals in health and disease. The Enterobacteriaceae are among the most important bacteria medically. A number of genera within the family are human intestinal pathogens (e.g. Salmonella, Shigella, Yersinia). Several others are normal colonists of the human gastrointestinal tract (e.g. Escherichia, Enterobacter, Klebsiella), but these bacteria, as well, may be associated with diseases of humans.

The Enterobacteriaceae are distinguished from the Pseudomonadaceae in a number of ways which must be recalled readily by competent microbiologists. The pseudomonads are respiratory, never fermentative, oxidase-positive, and motile by means of polar flagella. The enterics ferment glucose producing acid and gas, are typically oxidase-negative, and when motile, produce peritrichous flagella.

Physiologically, E. coli is versatile and well-adapted to its characteristic habitats. It can grow in media with glucose as the sole organic constituent. Wild-type E. coli has no growth factor requirements, and metabolically it can transform glucose into all of the macromolecular components that make up the cell. The bacterium can grow in the presence or absence of O2. Under anaerobic conditions it will grow by means of fermentation, producing characteristic "mixed acids and gas" as end products. However, it can also grow by means of anaerobic respiration, since it is able to utilize NO3, NO2 or fumarate as final electron acceptors for respiratory electron transport processes. In part, this adapts E. coli to its intestinal (anaerobic) and its extraintestinal (aerobic or anaerobic) habitats.

E. coli can respond to environmental signals such as chemicals, pH, temperature, osmolarity, etc., in a number of very remarkable ways considering it is a single-celled organism. For example, it can sense the presence or absence of chemicals and gases in its environment and swim towards or away from them. Or it can stop swimming and grow fimbriae that will specifically attach it to a cell or surface receptor. In response to change in temperature and osmolarity it can vary the pore diameter of its outer membrane porins to accommodate larger molecules (nutrients) or to exclude inhibitory substances. With its complex mechanisms for regulation of metabolism the bacterium can survey the chemical contents its environment in advance of synthesizing any enzymes necessary to use these compounds. It does not wastefully produce enzymes for degradation of carbon sources unless they are available, and it does not produce enzymes for synthesis of metabolites if they are available as nutrients in the environment.

E. coli is a consistent inhabitant of the human intestinal tract, and it is the predominant facultative organism in the human GI tract; however, it makes up a very small proportion of the total bacterial content. The number of anaerobic Bacteroides in the bowel outnumber E. coli by at least 20:1. The regular presence of E. coli in the human intestine and feces has led to tracking the bacterium in nature as an indicator of fecal pollution and water contamination. As such, it is taken to mean that, wherever E. coli is found, there may be fecal contamination by intestinal parasites of humans.

Pathogenesis of E. coli

Over 700 antigenic types or serotypes of E. coli have been recognized based on O, H, and K antigens. Serotyping is important in distinguishing the small number of strains that actually cause disease.

E. coli is responsible for three types of infections in humans: urinary tract infections (UTI), neonatal meningitis, and intestinal diseases (gastroenteritis). These three diseases depend on a specific array of pathogenic (virulence) determinants. The virulence determinants of various strains of pathogenic E. coli are summarized in Table 1.

Table 1. Summary of the Virulence Determinants of Pathogenic E. coli

Adhesins

Invasins

Motility/chemotaxis

flagella

Toxins

Antiphagocytic surface properties

Defense against serum bactericidal reaction

Defense against immune responses

Genetic attributes

Urinary tract infections

Uropathogenic E. coli causes 90% of the urinary tract infections (UTI) in anatomically-normal, unobstructed urinary tracts. The bacteria colonize from the feces or perineal region and ascend the urinary tract to the bladder. Bladder infections are 14-times more common in females than males by virtue of the shortened urethra. The typical patient with uncomplicated cystitis is a sexually-active female who was first colonized in the intestine with a uropathogenic E. coli strain. The organisms are propelled into the bladder from the periurethral region during sexual intercourse. With the aid of specific adhesins they are able to colonize the bladder.

The adhesin that has been most closely associated with uropathogenic E. coli is the P fimbria (or pyelonephritis-associated pili [PAP] pili). The letter designation is derived from the ability of P fimbriae to bind specifically to the P blood group antigen which contains a D-galactose-D-galactose residue. The fimbriae bind not only to red cells but to a specific galactose dissaccharide that is found on the surfaces uroepithelial cells in approximately 99% of the population.

The frequency of the distribution of this host cell receptor plays a role in susceptibility and explains why certain individuals have repeated UTI caused by E. coli. Uncomplicated E. coli UTI virtually never occurs in individuals lacking the receptors.

Uropathogenic strains of E. coli possess other determinants of virulence in addition to P fimbriae. E. coli with P fimbriae also possess the gene for Type 1 fimbriae, and there is evidence that P fimbriae are derived from Type 1 fimbriae by insertion of a new fimbrial tip protein to replace the mannose-binding domain of Type 1 fimbria. In any case, Type 1 fimbriae could provide a supplementary mechanism of adherence or play a role in aggregating the bacteria to a specific manosyl-glycoprotein that occurs in urine.

Uropathogenic strains of E. coli usually produce siderophores that probably play an essential role in iron acquisition for the bacteria during or after colonization. They also produce hemolysins which are cytotoxic due to formation of transmembranous pores in host cells. One strategy for obtaining iron and other nutrients for bacterial growth may involve the lysis of host cells to release these substances. The activity of hemolysins is not limited to red cells since the alpha-hemolysins of E. coli also lyse lymphocytes, and the beta-hemolysins inhibit phagocytosis and chemotaxis of neutrophils.

Another factor thought to be involved in the pathogenicity of the uropathogenic strains of E. coli is their resistance to the complement-dependent bactericidal effect of serum. The presence of K antigens is associated with upper urinary tract infections, and antibody to the K antigen has been shown to afford some degree of protection in experimental infections. The K antigens of E. coli are "capsular" antigens that may be composed of proteinaceous organelles associated with colonization (e.g., CFA antigens), or made of polysaccharides. Regardless of their chemistry, these capsules may be able to promote bacterial virulence by decreasing the ability of antibodies and/or complement to bind to the bacterial surface, and the ability of phagocytes to recognize and engulf the bacterial cells. The best studied K antigen, K-1, is composed of a polymer of N-acetyl neuraminic acid (sialic acid), which besides being antiphagocytic, has the additional property of being an antigenic disguise.

Neonatal Meningitis

Neonatal meningitis affects1/2,000-4,000 infants. Eighty percent of E. coli strains involved synthesize K-1 capsular antigens (K-1 is only present 20-40% of the time in intestinal isolates).

E. coli strains invade the blood stream of infants from the nasopharynx or GI tract and are carried to the meninges.

The K-1 antigen is considered the major determinant of virulence among strains of E. coli that cause neonatal meningitis. K-1 is a homopolymer of sialic acid. It inhibits phagocytosis, complement, and responses from the host's immunological mechanisms. K-1 may not be the only determinant of virulence, however, as siderophore production and endotoxin are also likely to be involved.

Epidemiologic studies have shown that pregnancy is associated with increased rates of colonization by K-1 strains and that these strains become involved in the subsequent cases of meningitis in the newborn. Probably the infant GI tract is the portal of entry into the bloodstream. Fortunately, although colonization is fairly common, invasion and the catastrophic sequelae are rare.

Neonatal meningitis requires antibiotic therapy that usually includes ampicillin and a third-generation cephalosporin.

Intestinal Diseases Caused by E. coli

As a pathogen, E. coli, of course, is best known for its ability to cause intestinal diseases. Five classes (virotypes) of E. coli that cause diarrheal diseases are now recognized: enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), and enteroaggregative E. coli (EAggEC). Each class falls within a serological subgroup and manifests distinct features in pathogenesis.

Enterotoxigenic E. coli

ETEC are an important cause of diarrhea in infants and travelers in underdeveloped countries or regions of poor sanitation. The diseases vary from minor discomfort to a severe cholera-like syndrome. ETEC are acquired by ingestion of contaminated food and water, and adults in endemic areas evidently develop immunity. The disease requires colonization and elaboration of one or more enterotoxins. Both traits are plasmid-encoded.

ETEC adhesins are fimbriae which are species-specific. For example, the K-88 fimbrial Ag is found on strains from piglets; K-99 Ag is found on strains from calves and lambs; CFA I, and CFA II, are found on strains from humans. These fimbrial adhesins adhere to specific receptors on enterocytes of the proximal small intestine.

Enterotoxins produced by ETEC include the LT(heat-labile) toxin and/or the ST (heat-stable) toxin, the genes for which may occur on the same or separate plasmids. The LT enterotoxin is very similar to cholera toxin in both structure and mode of action. It is an 86kDa protein composed of an enzymatically active (A) subunit surrounded by 5 identical binding (B) subunits. It binds to the same identical ganglioside receptors that are recognized by the cholera toxin (i.e., GM1), and its enzymatic activity is identical to that of the cholera toxin.

The ST enterotoxin is actually a family of toxins which are peptides of molecular weight about 2,000 daltons. Their small size explains why they are not inactivated by heat. ST causes an increase in cyclic GMP in host cell cytoplasm leading to the same effects as an increase in cAMP. STa is known to act by binding to a guanylate cyclase that is located on the apical membranes of host cells, thereby activating the enzyme. This leads to secretion of fluid and electrolytes resulting in diarrhea.

Symptoms ETEC infections include diarrhea without fever. The bacteria colonize the GI tract by means of a fimbrial adhesin, e.g. CFA I and CFA II, and are noninvasive, but produce either the LT or ST toxin.

Enteroinvasive E. coli

EIEC closely resemble Shigella in their pathogenic mechanisms and the kind of clinical illness they produce. EIEC penetrate and multiply within epithelial cells of the colon causing widespread cell destruction. The clinical syndrome is identical to Shigella dysentery and includes a dysentery-like diarrhea with fever. EIEC apparently lack fimbrial adhesins but do possess a specific adhesin that, as in Shigella, is thought to be an outer membrane protein. Also, likeShigella, EIEC are invasive organisms. They do not produce LT or ST toxin and, unlike Shigella, they do not produce the shiga toxin.

Enteropathogenic E. coli

EPEC induce a watery diarrhea similar to ETEC, but they do not possess the same colonization factors and do not produce ST or LT toxins. They produce a non fimbrial adhesin designated intimin, an outer membrane protein, that mediates the final stages of adherence. They do not produce LT or ST toxins, but there are reports that they produce an enterotoxin similar to that of Shigella. Other virulence factors may be related to those in Shigella.

Adherence of EPEC strains to the intestinal mucosa is a very complicated process and produces dramatic effects in the ultrastructure of the cells resulting in rearrangements of actin in the vicinity of adherent bacteria. The phenomenon is sometimes called "attaching and effacing" of cells. EPEC strains are said to be "moderately-invasive" meaning they are not as invasive as Shigella, and unlike ETEC or EAggEC, they cause an inflammatory response. The diarrhea and other symptoms of EPEC infections probably are caused by bacterial invasion of host cells and interference with normal cellular signal transduction, rather than by production of toxins.

Some types of EPEC are referred to as Enteroadherent E. coli (EAEC), based on specific patterns of adherence. They are an important cause of traveler's diarrhea in Mexico and in North Africa.

Enteroaggregative E. coli

The distinguishing feature of EAggEC strains is their ability to attach to tissue culture cells in an aggregative manner. These strains are associated with persistent diarrhea in young children. They resemble ETEC strains in that the bacteria adhere to the intestinal mucosa and cause non-bloody diarrhea without invading or causing inflammation. This suggests that the organisms produce a toxin of some sort. Recently, a distinctive heat-labile plasmid-encoded toxin has been isolated from these strains, called the EAST (EnteroAggregative ST) toxin. They also produce a hemolysin related to the hemolysin produced by E. coli strains involved in urinary tract infections. The role of the toxin and the hemolysin in virulence has not been proven. The significance of EAggEC strains in human disease is controversial.

Enterohemorrhagic E. coli

EHEC are represented by a single strain (serotype O157:H7), which causes a diarrheal syndrome distinct from EIEC (and Shigella) in that there is copious bloody discharge and no fever. A frequent life-threatening situation is its toxic effects on the kidneys (hemolytic uremia).

EHEC has recently been recognized as a cause of serious disease (e.g. the Jack-in-the-Box outbreak in the Northwest). Pediatric diarrhea caused by this strain can be fatal due to acute kidney failure (hemolytic uremic syndrome [HUS]). EHEC are also considered to be "moderately invasive". Nothing is known about the colonization antigens of EHEC but fimbriae are presumed to be involved. The bacteria do not invade mucosal cells as readily as Shigella, but EHEC strains produce a toxin that is virtually identical to the Shiga toxin. The toxin plays a role in the intense inflammatory response produced by EHEC strains and may explain the ability of EHEC strains to cause HUS. The toxin is phage encoded and its production is enhanced by iron deficiency.

Table 2. Pathogenic E. coli: Summary of Characteristics of Intestinal Pathogens

ETEC

EIEC

EPEC

EAggEC

EHEC

Bacterial Diseases

	Protein Toxins
	Endotoxins
	Anthrax (General Information), (Technical Information)
	Botulism and Tetanus
	Chlamydia
	Cholera
	Diphtheria
	E. coli
	Helicobacterium pylori
	Lyme Disease
	Whooping Cought
	Pseudomonas
	Staphylococcus
	Streptococcus
	Syphilis
	Tuberculosis