Escherichia coli

Enterotoxigenic Escherichia coli

ETEC accounts for a sizable fraction of dehydrating infantile diarrhea in the developing world (10–30%) and of traveler's diarrhea (20–60% of cases); ETEC is the most common cause of traveler's diarrhea. In the Global Enteric Multicenter Study (GEMS) conducted across Asia and Africa, heat-stable enterotoxin (ST)–expressing ETEC (with or without coexpression of heat-labile enterotoxin [LT]) was among the most important causes of diarrhea in young children in developing countries and was associated with increased risk of death. The typical signs and symptoms include explosive watery, nonmucoid, nonbloody diarrhea; abdominal pain; nausea; vomiting; and little or no fever. The illness is usually self-limited and resolves in 3-5 days but occasionally lasts >1 wk.

ETEC causes few or no structural alterations in the gut mucosa. Diarrhea follows colonization of the small intestine and elaboration of enterotoxins. ETEC strains secrete an LT and/or an ST. LT, a large molecule consisting of 5 receptor-binding subunits and 1 enzymatically active subunit, is structurally, functionally, and neutralizing antibody cross-reactive with cholera toxin produced by Vibrio cholerae . LT stimulates adenylate cyclase, resulting in increased cyclic adenosine monophosphate. ST is a small molecule not related to cholera toxin. ST stimulates guanylate cyclase, resulting in increased cyclic guanosine monophosphate. Each toxin induces ion and water secretion into the intestinal lumen, resulting in profuse watery diarrhea. The genes for these toxins are encoded on plasmids.

Colonization of the intestine requires fimbrial colonization factor antigens (CFAs) , which promote adhesion to the intestinal epithelium. Over 25 CFA types exist and can be expressed alone or in combinations. Prevalent colonization factors include CFA/I, CS1-CS7, CS14, and CS17. However, CFAs have not been detected on all ETEC strains. Although 30–50% of ETEC isolates have no characterized CFA by phenotypic screening, novel CFAs continue to be identified. CFAs are highly immunogenic. However, the multiple CFAs and their allelic variants have made the definition of immunity and development of useful vaccines difficult. A large proportion of strains produce a type IV pilus called longus , which functions as a colonization factor and is found among several other gram-negative bacterial pathogens. ETEC strains also have the common pilus, produced by commensal and pathogenic E. coli strains. Among the nonfimbrial adhesions, TibA is a potent bacterial adhesin that mediates bacterial attachment and invasion of cells. For many years, the O serogroup was used to distinguish pathogenic from commensal E. coli . Because the pathogenic E. coli are now defined and classified by using probes or primers for specific virulence genes, determining the O serogroup has become less important. Of the >180 E. coli serogroups, only a relatively small number typically are ETEC. The most common O groups are O6, O8, O128, and O153, and based on some large retrospective studies, these serogroups account for only half the ETEC strains.

Enteroinvasive Escherichia coli

Clinically, EIEC infections present either with watery diarrhea or a dysentery syndrome with blood, mucus, and leukocytes in the stools, as well as fever, systemic toxicity, crampy abdominal pain, tenesmus, and urgency. The illness resembles bacillary dysentery because EIEC shares virulence genes with Shigella spp. Sequencing of multiple housekeeping genes indicates that EIEC is more related to Shigella than to noninvasive E. coli . EIEC diarrhea occurs mostly in outbreaks; however, endemic disease occurs in developing countries. In some areas of the developing world as many as 5% of sporadic diarrhea episodes and 20% of bloody diarrhea cases are caused by EIEC (see Chapter 226 ).

EIEC disease resembles shigellosis . EIEC cause colonic lesions with ulcerations, hemorrhage, mucosal and submucosal edema, and infiltration by polymorphonuclear leukocytes (PMNs). EIEC strains behave like Shigella in their capacity to invade gut epithelium and produce a dysentery-like illness. The invasive process involves initial entry into cells, intracellular multiplication, intracellular and intercellular spread, and host cell death. All bacterial genes necessary for entry into the host cell are clustered within a 30-kb region of a large virulence plasmid; these genes are closely related to those found on the invasion plasmid of Shigella spp. This region carries genes encoding the entry-mediating proteins, including proteins that form a needle-like injection apparatus called type III secretion, required for secreting the invasins (IpaA-D and IpgD). The Ipas are the primary effector proteins of epithelial cell invasion. The type III secretion apparatus is a system triggered by contact with host cells; bacteria use it to transport proteins into the host cell plasma membrane and inject toxins into the host cell cytoplasm.

EIEC encompasses a small number of serogroups (O28ac, O29, O112ac, O124, O136, O143, O144, O152, O159, O164, O167, and some untypeable strains). These serogroups have LPS antigens related to Shigella LPS, and as with shigellae, are nonmotile (they lack H or flagellar antigens) and are usually non–lactose fermenting.

Enteropathogenic Escherichia coli

EPEC causes acute, prolonged, and persistent diarrhea, primarily in children <2 yr old in developing countries, where the organism may account for 20% of infant diarrhea. In developed countries, EPEC cause occasional daycare center and pediatric ward outbreaks. Profuse watery, nonbloody diarrhea with mucus, vomiting, and low-grade fever are common symptoms. Prolonged diarrhea (>7 days) and persistent diarrhea (>14 days) can lead to malnutrition , a potentially mortality-associated outcome of EPEC infection in infants in the developing world. Studies show that breastfeeding is protective against diarrhea caused by EPEC.

EPEC colonization causes blunting of intestinal villi, local inflammatory changes, and sloughing of superficial mucosal cells; EPEC-induced lesions extend from the duodenum through the colon. EPEC induces a characteristic attaching and effacing histopathologic lesion, which is defined by the intimate attachment of bacteria to the epithelial surface and effacement of host cell microvilli. Factors responsible for the attaching and effacing lesion formation are encoded by the locus of enterocyte effacement (LEE), a pathogenicity island with genes for a type III secretion system, the translocated intimin receptor (Tir) and intimin, and multiple effector proteins such as the E. coli –secreted proteins (EspA-B-D). Some strains adhere to the host intestinal epithelium in a pattern known as localized adherence , a trait that is mediated in part by the type IV bundle-forming pilus (Bfp) encoded by a plasmid (the EAF plasmid). After initial contact, proteins are translocated through filamentous appendages forming a physical bridge between the bacteria and the host cell; bacterial effectors (EspB, EspD, Tir) are translocated through these conduits. Tir moves to the surface of host cells, where it is bound by a bacterial outer membrane protein intimin (encoded by the eae gene). Intimin-Tir binding triggers polymerization of actin and other cytoskeletal components at the site of attachment. These cytoskeletal changes result in intimate bacterial attachment to the host cell, enterocyte effacement, and pedestal formation.

Other LEE-encoded effectors include Map, EspF, EspG, EspH, and SepZ. Various other effector proteins are encoded outside the LEE and secreted by the type III secretion system (the non–LEE-encoded proteins, or Nle). The contribution of these putative effectors (NleA/EspI, NleB, NleC, NleD, etc.) to virulence is still under investigation. The presence and expression of virulence genes vary among EPEC strains.

The eae (intimin) and bfp A genes are useful for identifying EPEC and for subdividing this group of bacteria into typical and atypical strains. E. coli strains that are eae ⁺ / bfp A ⁺ are classified as “typical” EPEC; most of these strains belong to common O:H serotypes. E. coli strains that are eae ⁺ / bfp A ⁻ are classified as “atypical” EPEC. Typical EPEC has been considered for many years to be a leading cause of infantile diarrhea in developing countries and was considered rare in industrialized countries. However, current data suggest that atypical EPEC are more prevalent than typical EPEC in both developed and developing countries, even in persistent diarrhea cases. Determining which of these heterogeneous strains are true pathogens remains a work in progress. In the GEMS, typical EPEC was the main pathogen associated with increased risk of mortality, particularly in infants in Africa.

The classic EPEC serogroups include strains of 12 O serogroups: O26, O55, O86, O111, O114, O119, O125, O126, O127, O128, O142, and O158. However, various E. coli strains defined as EPEC based on the presence of the intimin gene belong to nonclassic EPEC serogroups, especially the atypical strains.