In vivo expression of the heat stable (estA) and heat labile (eltB) toxin genes of enterotoxigenic Escherichia coli (ETEC)

Sjöling, Åsa; Qadri, Firdausi; Nicklasson, Matilda; Begum, Yasmin; Wiklund, Gudrun; Svennerholm, Ann‐Mari

doi:10.1016/j.micinf.2006.08.011

Cited by 26 publications

(24 citation statements)

References 23 publications

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“…ETEC colonization of the small intestine is facilitated by CF-mediated mucosal adhesion. Thereupon, the colonizing strain expresses its enterotoxins, though expression levels do not seem to be influenced by colonization (46). In the intestine, ST binds to and activates the intestinal brush border guanylate-cyclase-C (GC-C) receptor, which is the receptor of the endogenous ligands guanylin and uroguanylin (15,43,56,57).…”

Section: St Biologymentioning

confidence: 99%

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

et al. 2010

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5Enterotoxigenic Escherichia coli (ETEC) is responsible for 280 million to 400 million episodes of diarrhea and about 380,000 deaths annually. Epidemiological data suggest that ETEC strains which secrete heat-stable toxin (ST), alone or in combination with heat-labile toxin (LT), induce the most severe disease among children in developing countries. This makes ST an attractive target for inclusion in an ETEC vaccine. ST is released upon colonization of the small intestine and activates the guanylate cyclase C receptor, causing profuse diarrhea. To generate a successful toxoid, ST must be made immunogenic and nontoxic. Due to its small size, ST is nonimmunogenic in its natural form but becomes immunogenic when coupled to an appropriate large-molecular-weight carrier. This has been successfully achieved with several carriers, using either chemical conjugation or recombinant fusion techniques. Coupling of ST to a carrier may reduce toxicity, but further reduction by mutagenesis is desired to obtain a safe vaccine. More than 30 ST mutants with effects on toxicity have been reported. Some of these mutants, however, have lost the ability to elicit neutralizing immune responses to the native toxin. Due to the small size of ST, separating toxicity from antigenicity is a particular challenge that must be met. Another obstacle to vaccine development is possible cross-reactivity between anti-ST antibodies and the endogenous ligands guanylin and uroguanylin, caused by structural similarity to ST. Here we review the molecular and biological properties of ST and discuss strategies for developing an ETEC vaccine that incorporates immunogenic and nontoxic derivatives of the ST toxin.

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Section: St Biologymentioning

confidence: 99%

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

et al. 2010

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“…Many strains of ETEC elaborate a virulence factor called heat-labile enterotoxin or LT (34). LT is an AB 5 toxin, consisting of a single A subunit, LTA, and a ring of five B subunits, LTB (33).…”

mentioning

confidence: 99%

Residues of Heat-Labile Enterotoxin Involved in Bacterial Cell Surface Binding

Mudrak¹,

Rodriguez

Kuehn

2009

J Bacteriol

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Enterotoxigenic Escherichia coli (ETEC) is a leading cause of traveler's diarrhea worldwide. One major virulence factor released by this pathogen is the heat-labile enterotoxin LT, which upsets the balance of electrolytes in the intestine. After export, LT binds to lipopolysaccharide (LPS) on the bacterial surface. Although the residues responsible for LT's binding to its host receptor are known, the portion of the toxin which mediates LPS binding has not been defined previously. Here, we describe mutations in LT that impair the binding of the toxin to the external surface of E. coli without altering holotoxin assembly. One mutation in particular, T47A, nearly abrogates surface binding without adversely affecting expression or secretion in ETEC. Interestingly, T47A is able to bind mutant E. coli expressing highly truncated forms of LPS, indicating that LT binding to wild-type LPS may be due primarily to association with an outer core sugar. Consequently, we have identified a region of LT distinct from the pocket involved in eukaryotic receptor binding that is responsible for binding to the surface of E. coli.Enterotoxigenic Escherichia coli (ETEC), a common etiologic agent behind traveler's diarrhea, is also a significant cause of mortality worldwide (38). Many strains of ETEC elaborate a virulence factor called heat-labile enterotoxin or LT (34). LT is an AB 5 toxin, consisting of a single A subunit, LTA, and a ring of five B subunits, LTB (33). LTB mediates the toxin's binding properties, and LTA ADP ribosylates host G proteins, increasing levels of cyclic AMP and causing the efflux of electrolytes and water into the intestinal lumen (27,35). Each subunit of LT is translated separately from a bicistronic message and then transported to the periplasm, where holotoxin assembly spontaneously occurs (16). Subsequent export into the extracellular milieu is carried out by the main terminal branch of the general secretory pathway (31,36).LT binds eukaryotic cells via an interaction between LTB and host gangliosides, primarily the monosialoganglioside GM 1 (35). The binding site for GM 1 , situated at the interface of two B subunits, has been identified by crystallography (26). GM 1 binding can be strongly impaired by a point mutation in LTB that converts Gly-33 to an aspartic acid residue (37). LT is highly homologous to cholera toxin (CT), both in sequence and structure (7, 35), contributing to ETEC's potentially cholera-like symptoms (39).Previous work in our lab has demonstrated that LT possesses an additional binding capacity beyond its affinity for host glycolipids: the ability to associate with lipopolysaccharide (LPS) on the surface of E. coli (20). LPS, the major component of the outer leaflet of the gram-negative outer membrane, consists of a characteristic lipid moiety, lipid A, covalently linked to a chain of sugar residues (30). In bacteria like E. coli, this sugar chain can be further divided into an inner core oligosaccharide of around five sugars, an outer core of four to six additional sugars, and in ...

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“…The expression of TCP and CT in a spatiotemporal manner within the small intestine (78) suggests that the enterocyte environment is actively modified by the toxin, setting the stage for vibrio binding and colonization on the enterocyte surface via TCP. ETEC organisms likely follow a similar pattern of gene expression in response to environmental stimuli to render the organism suitable for colonization, although little is known regarding in vivo triggers for LT toxin expression at this time (20,83,92). …”

Section: Regulation Of Toxin Elaborationmentioning

confidence: 99%

Toxin-Mediated Effects on the Innate Mucosal Defenses: Implications for Enteric Vaccines

Glenn¹,

Francis

Danielsen³

2009

Infect Immun

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3Recent studies have confirmed older observations that the enterotoxins enhance enteric bacterial colonization and pathogenicity. How and why this happens remains unknown at this time. It appears that toxins such as the heat-labile enterotoxin (LT) from Escherichia coli can help overcome the innate mucosal barrier as a key step in enteric pathogen survival. We review key observations relevant to the roles of LT and cholera toxin in protective immunity and the effects of these toxins on innate mucosal defenses. We suggest either that toxin-mediated fluid secretion mechanically disrupts the mucus layer or that toxins interfere with innate mucosal defenses by other means. Such a breach gives pathogens access to the enterocyte, leading to binding and pathogenicity by enterotoxigenic E. coli (ETEC) and other organisms. Given the common exposure to LT

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In vivo expression of the heat stable (estA) and heat labile (eltB) toxin genes of enterotoxigenic Escherichia coli (ETEC)

Cited by 26 publications

References 23 publications

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

Heat-Stable Enterotoxin of EnterotoxigenicEscherichia colias a Vaccine Target

Residues of Heat-Labile Enterotoxin Involved in Bacterial Cell Surface Binding

Toxin-Mediated Effects on the Innate Mucosal Defenses: Implications for Enteric Vaccines

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