EHEC: Since the early 1980s, EHEC has become a cause celebre with E coli 0157:H7 — a familiar household fear-inducing term. There are striking similarities between EPEC and EHEC. The most obvious similarity is the ability to form the intimate type of adhesion pedestal; the A/E lesion is readily demonstrable in conventional and gnotobi-otic pigs, infant rabbits and cultured cells, but not in humans because this facet of the disease occurs early and biopsies are taken (and only when clinically warranted) later in the infection when A/E lesions would be missed. EHEC possesses LEE, the genetic organization of which is the same in both EPEC and EHEC, with 93.9% average nucleotide identity. However, the gene encoding intimin is less conserved (87.23%; see below), and those encoding the secreted proteins including Tir are quite divergent. Such analyses are of more than mere academic interest because an understanding of the biochemical basis of the host and tissue specificities exhibited by pathogens provides a basis for effective vaccine development. However, there are significant differences between EPEC and EHEC. buy ortho tri-cyclen
Unlike EPEC, EHEC is essentially a pathogen of the large intestine. It is now known that intimin is not a single molecular entity but a family comprising at least four anti-genically distinct subtypes — alpha, beta, gamma and delta. The divergent C-termini of these multifunctional intimins contain the cell-binding domains. This diversity had been proposed as an explanation for the tissue tropism exhibited by EHEC, which shows a predilection for colonizing the colon as opposed to the small bowel. These ideas were given credence by the demonstration of an ability to alter the site(s) of colonization of EHEC in gnotobiotic pigs by substituting EPEC genes for their equivalent in EHEC. However, it is unlikely that tissue specificity is explicable in terms of intimin-Tir interaction, if for no other reason than that the main receptor for intimin, Tir, is itself a bacterial protein. Recent detailed structural and genetic studies on intimins show intimin to comprise three separate domains: two immunoglobulin-like domains and a C-type lectin-like domain. From detailed intimin-Tir studies, it was concluded that intimin-Tir interaction cannot explain tissue/species specificity; it is more likely that tissue tropism is determined by an initial lectin-like recognition of a specific cell receptor by intimin. Other systems may also be involved because some strains of E coli have been isolated from human cases of hemolytic uremic syndrome (HUS), which belong to serotypes other than O157:H7. Another important difference between EHEC and EPEC is that EHEC does not possess EAF, hence no per gene homo-logues; the regulation of LEE in EHEC is not known. The vast majority of EHEC strains possess a 60 MDa plasmid, which also encodes an enterohemolysin and a fimbrial antigen, but the significance of these and other plasmid-encoded genes in the pathogenesis of EHEC-induced disease is unclear at present.
Easily, the most important distinguishing feature of EHEC is the capacity to progress disease beyond the watery diarrhea stage to a grossly bloody diarrhea (hemorrhagic colitis [HC]) and HUS, which is characterized by renal failure, thrombocytopenia and microangiopathic hemolytic anemia. This virulence attribute is due to possession of one or more of a family of Shiga toxin(s) (Stx), which are encoded by lysogenic lambdoid phages. Stx1 is identical to Stx of Shigella dysenteriae I (which is not phage encoded) and is highly conserved, whereas a variety of subtypes of Stx2 exist. The role of Stx in the causation of watery diarrhea is controversial, and it may not be absolutely necessary. However, there is no doubt that Stx is either responsible for, or severely exacerbates the bloody diarrhea in HC. Sjogren et al orally challenged young rabbits with rabbit diarrheagenic E coli (RDEC-1) (a rabbit strain of EPEC) and an Stx-positive RDEC-1 derivative; the disease resulting from the Stx-positive strain was much more severe. This echoed earlier work in which monkeys were orally challenged with wild-type S dysenteriae I and a Stx-negative derivative of S dysenteriae I. In both groups, diarrhea occurred, but with the wild-type strain, there was distinctly greater tissue hemorrhage and more bloody stools. Unfortunately, there are no suitable animal models for HUS, but a body of persuasive indirect evidence has been marshalled, which implicates Stx as the principal causative agent of HUS. More importantly, others have recently made the first histochemical demonstration of both Stx1 and Stx2 bound to renal tubules in the kidney of a child who died as a result of HUS associated with E coli O157:H7 infection.