Vibrio cholerae: V cholerae colonizes the upper small intestine by adhering to epithelial cells. Despite being arguably the most studied pathogen over the past three decades, the basis of V cholerae pathogenicity and the detailed mechanisms underlying the dramatic diarrheal secretion induced by this organism are still not fully understood. Recently, spectacular advances have been made in the molecular biology of V cholerae. Chromosomal DNA of virulent
V cholerae contains two essential genetic elements that are important in V cholerae virulence: СТХф (the genome of a filamentous bacteriophage), which encodes the cholera toxin (CT), and a large pathogenicity island, the V cholerae pathogenicity island (VPI). VPI is now known to be the integrated genome of another large filamentous bacteriophage (VPty) and encodes the toxin coregulated type IV pilus (Tcp). Of the numerous colonization factors known to be produced by V cholerae, only Tcp has been proven to be important in human disease. Tcp is a remarkable entity; its subunit TcpA is a coat protein of VP% but it also acts as a receptor for CTXф and mediates interbacterial adherence. Thus, as a result of sequential infection by two ‘pathophages’, V cholerae acquires the ability to colonize the human gut and secrete classical CT, which is a potent enterotoxin. The integration into the chromosome of these phage genomes brings their expression under the control of regulatory genes in the ancestral chromosome, while the replication of phages enables their interbacterial spread.
CT is an ‘AB’ type toxin in which the pentameric B subunit recognizes and binds to its cell receptor (GM1 ganglio-side), thereby initiating the internalization of the active A subunit (CTA). The enzymatically active A reaches its intracellular target by ‘co-opting the molecular machinery used by the host cell to sort, move and organize cellular membranes and substituent components’. The activity of CTA is well known: it catalyses the ADP-ribosylation of the regulatory alpha subunit of adenylate cyclase, causing the elevation of cAMP. This in turn gives rise to a biochemical cascade, resulting in the perturbation of ion transport systems and the reversal of net ion transport/fluid across epithelial cells. This summary statement of such elegant work implies that cholera diarrhea is a purely pathophysiological disease, but that is too simplistic. birth control pills
While the major diarrheagenic toxin is undoubtedly classical CT, there are at least eight other toxins that have been potentially implicated in cholera diarrhea. There is some evidence of involvement in human disease for one of these. A zonula occludens toxin of V cholerae has been described, which alters the permeability of rabbit epithelia. It has been suggested that the zonula occludens toxin might be responsible for the alteration in apical junctional complexes observed in human duodenal biopsies from cholera patients. However, it is the zonula adherens in human tissue and not the tight (occludens) junction that is affected by V cholerae, and this emphasizes the care needed when extrapolating data from model systems to actual disease situations. Moreover, the studies on human jejunal biopsies show that cholera is not a purely pathophysiological disease but a pathological one involving changes in the microvasculature and enteric nerve fibres, degranulation of argentaffin cells, mucosal mast cells and eosinophils; the extent of these changes correlated with clinical severity of disease. A V cholerae vaccine strain produced by the deletion/mutation of all known toxin genes yielded a vaccine strain, which, though less reacto-genic than wild-type virulent strains, still produced a significant diarrhea suggesting the involvement of an inflammatory component (as yet undefined) in the causation of cholera diarrhea. There is also experimental evidence to implicate the ENS in cholera diarrhea. It has also been shown that CT administered to rat jejunum elicited a secretory response in both the jejunum and colon, which suggests neurological transmission of the locally induced secretory stimulus to distal colon.
E coli: It is essential to be reminded of the different pathotypes of E coli, all of which, except for one (enteroinvasive E coli [EIEC], which is almost identical to Shigella species) are noninvasive. These pathotypes are enterotoxigenic E coli (ETEC); EPEC, which are characterized by localized adherence of organisms to HEp-2 cells; enterohemorrhagic E coli (EHEC); two types of enteroaggregative E coli (EAEC), which are characterized by aggregative adherence of organisms to HEp-2 cells and to each other in a stacked brick configuration; and diffusely adhering E coli (DAEC), which are characterized by diffuse monolayered adherence of organisms to HEp-2 cells. Because these different E coli pathotypes and the pathogenesis of disease they cause have been comprehensively reviewed, only a brief general outline is given here, with newer developments being highlighted. Uropathogenic E coli (UPEC) is referred to only in passing, and EIEC is not dealt with separately because of its relatedness to Shigella species. Necrotoxigenic E coli are also excluded from this review.