Zinc and the Heat-Labile Enterotoxin of Escherichia Coli

Sugarman, Barrett; Epps, Lisa R.

doi:10.1099/00222615-18-3-393

Cited by 7 publications

(4 citation statements)

References 7 publications

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“…These results support and extend the findings of Long-Krug et al (1984) by showing that the use of various culture media or iron depleted media and the addition of zinc ions or lincomycin, factors which affect toxin production by other intestinal pathogens (Levner et al, 1977;Mundellet al, 1976;O'Brienet al, 1982;Sugarman and Epps, 1984;Iwanaga and Yamamoto, 1984), do not stimulate enterotoxin production by EPEC strains.…”

Section: Discussionsupporting

confidence: 80%

“…The media were also prepared containing either lincomycin 90mg/L or ~O-'M zinc chloride; both treatments enhance LT production by ETEC strains (Levner et al, 1977;Sugarman and Epps, 1984). Media were dispensed in 50-ml volumes in 250-ml Erlenmeyer flasks and seeded with 200 pl of an overnight culture of the E. coli strain grown in Nutrient Broth (Oxoid).…”

Section: Mediamentioning

confidence: 99%

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Examination of enteropathogenic Escherichia coli strains for an adenylcyclase stimulating factor

Law¹,

Wilkie²,

Freeman³

1987

Journal of Medical Microbiology

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Summary. Enteropathogenic Escherichia coli strains are a common cause of infantile diarrhoea but do not produce recognised enterotoxins. Three strains of proven virulence were examined for toxins which may be missed in conventional tests. Cell lysates and concentrated culture supernates of organisms grown in five different media gave negative results when examined for adenylcyclase stimulating activity. The additions of zinc ions or lincomycin to these media or the use of iron-depleted media also gave negative results. The significance of these findings and the possible role of other toxins in diarrhoea due to enteropathogenic E. coli are discussed.

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Section: Discussionsupporting

confidence: 80%

Section: Mediamentioning

confidence: 99%

Examination of enteropathogenic Escherichia coli strains for an adenylcyclase stimulating factor

Law¹,

Wilkie²,

Freeman³

1987

Journal of Medical Microbiology

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“…jejuni shows reduced pathogenicity in the chick model in absence of the zinc transporter, ZnuA [ 54 ]. Similarly, LT toxin secretion may be increased in the presence of zinc [ 22 ]. Although CFA/I was inhibited by 1,10-phenanthroline, it was also inhibited in presence of 25 μM excess zinc.…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Components Influencing Colonization Factor Antigen I Expression in Enterotoxigenic Escherichia coli

et al. 2015

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Colonization factors (CFs) mediate early adhesion of Enterotoxigenic Escherichia coli (ETEC) in the small intestine. Environmental signals including bile, glucose, and contact with epithelial cells have previously been shown to modulate CF expression in a strain dependent manner. To identify novel components modulating CF surface expression, 20 components relevant to the intestinal environment were selected for evaluation. These included mucin, bicarbonate, norepinephrine, lincomycin, carbon sources, and cations. Effects of individual components on surface expression of the archetype CF, CFA/I, were screened using a fractional factorial Hadamard matrix incorporating 24 growth conditions. As most CFs agglutinate erythrocytes, surface expression was evaluated by mannose resistant hemagglutination. Seven components, including porcine gastric mucin, lincomycin, glutamine, and glucose were found to induce CFA/I surface expression in vitro in a minimal media while five others were inhibitory, including leucine and 1,10-phenanthroline. To further explore the effect of components positively influencing CFA/I surface expression, a response surface methodology (RSM) was designed incorporating 36 growth conditions. The optimum concentration for each component was identified, thereby generating a novel culture media, SP1, for CFA/I expression. CFs closely related to CFA/I, including CS4 and CS14 were similarly induced in SP1 media. Other epidemiologically relevant CFs were also induced when compared to the level obtained in minimal media. These results indicate that although CF surface expression is complex and highly variable among strains, the CF response can be predicted for closely related strains. A novel culture media inducing CFs in the CF5a group was successfully identified. In addition, mucin was found to positively influence CF expression in strains expressing either CFA/I or CS1 and CS3, and may function as a common environmental cue.

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“…IscR and iron mediate virulence in Shigella flexneri, Erwinia chrysanthemi, and Pseudomonas aeruginosa (28)(29)(30). Zinc induces the production of LT in some ETEC isolates (31), and zinc supplementation does not generally impact ETEC viability or adhesion to host epithelia yet alters the transcriptome of ETEC and the host (32,33).…”

mentioning

confidence: 99%

Enterotoxigenic Escherichia coli Heat-Stable Toxin Increases the Rate of Zinc Release from Metallothionein and Is a Zinc- and Iron-Binding Peptide

Kiefer

Motyka

Clements

et al. 2020

mSphere

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Enterotoxigenic Escherichia coli (ETEC) is a major diarrheal pathogen in children in low- to middle-income countries. Previous studies have identified heat-stable enterotoxin (ST)-producing ETEC as one of the major diarrhea-causing pathogens in children younger than five years. In this study, we examined iron and zinc binding by both human and porcine ST variants and determined how host metallothionein could detoxify ST. We found that ST purified from ETEC culture supernatants eluted as a doublet during C18 reverse-phase chromatography. Leading edge fractions of the ST doublet were found to be devoid of iron, while trailing edge fractions of the ST doublet were found to contain measurable iron. Next, we found that purified ST could be reconstituted with iron under reducing and anaerobic conditions, and iron-bound ST attenuated the induction of cGMP in T84 epithelial cells. Moreover, we demonstrated that supernatants of ETEC 214-4 grown under increasing iron concentrations were only able to induce cGMP at iron concentrations greater than 5 μM. In vitro studies also demonstrated that ST binds zinc, and once bound, zinc removal from ST required denaturing conditions. Zinc-bound ST also failed to induce cGMP. We found that ST contributes disulfide bonds to the perceived oxidized glutathione pool, increases the rate of zinc release from metallothionein, and can be detoxified by metallothionein. Lastly, we showed ST induces transcriptional changes in genes previously shown to be regulated by deferoxamine. These studies demonstrate ST ETEC pathogenesis may be tied intimately to host mucosal metal status. IMPORTANCE Enterotoxigenic Escherichia coli (ETEC) is a major diarrheal pathogen in children in low- to middle-income countries, deployed military personnel, and travelers to regions of endemicity. The heat-stable toxin (ST) is a small nonimmunogenic secreted peptide with 3 disulfide bonds. It has been appreciated that dietary disulfides modulate intestinal redox potential and that ST could be detoxified using exogenous reductants. Using biochemical and spectroscopic approaches, we demonstrated that ST can separately bind iron and zinc under reducing conditions, thereby reducing ST toxicity. Moreover, we demonstrated that ST modulates the glutathione (GSH)/oxidized glutathione (GSSG) ratio and that ST should be considered a toxin oxidant. ST can be detoxified by oxidizing zinc-loaded metallothionine, causing free zinc to be released. These studies help lay a foundation to understand how diarrheal pathogens modulate intestinal redox potential and may impact how we design therapeutics and/or vaccines for the pathogens that produce them.

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Zinc and the Heat-Labile Enterotoxin of Escherichia Coli

Cited by 7 publications

References 7 publications

Examination of enteropathogenic Escherichia coli strains for an adenylcyclase stimulating factor

Examination of enteropathogenic Escherichia coli strains for an adenylcyclase stimulating factor

Identification of Novel Components Influencing Colonization Factor Antigen I Expression in Enterotoxigenic Escherichia coli

Enterotoxigenic Escherichia coli Heat-Stable Toxin Increases the Rate of Zinc Release from Metallothionein and Is a Zinc- and Iron-Binding Peptide

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