Failure of Manganese to Protect from Shiga Toxin

Gaston, Marsha A.; Pellino, Christine A.; Weiss, Alison A.

doi:10.1371/journal.pone.0069823

Cited by 14 publications

(10 citation statements)

References 30 publications

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“…Hope that manganese could be used as a treatment for STEC infection diminished, however, when Gaston et al and additional work by Mukhopadhyay et al showed that the protective effects of manganese did not extend to Stx2 [65,66]. Gaston and colleagues also showed that manganese was more toxic, both in cultured cells and in mice, than was reported by Mukhopadhyay and Linstedt.…”

Section: Discussionmentioning

confidence: 99%

Zinc protects against shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria

et al. 2014

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BackgroundZinc supplements can treat or prevent enteric infections and diarrheal disease. Many articles on zinc in bacteria, however, highlight the essential nature of this metal for bacterial growth and virulence, suggesting that zinc should make infections worse, not better. To address this paradox, we tested whether zinc might have protective effects on intestinal epithelium as well as on the pathogen.ResultsUsing polarized monolayers of T84 cells we found that zinc protected against damage induced by hydrogen peroxide, as measured by trans-epithelial electrical resistance. Zinc also reduced peroxide-induced translocation of Shiga toxin (Stx) across T84 monolayers from the apical to basolateral side. Zinc was superior to other divalent metals to (iron, manganese, and nickel) in protecting against peroxide-induced epithelial damage, while copper also showed a protective effect.The SOS bacterial stress response pathway is a powerful regulator of Stx production in STEC. We examined whether zinc’s known inhibitory effects on Stx might be mediated by blocking the SOS response. Zinc reduced expression of recA, a reliable marker of the SOS. Zinc was more potent and more efficacious than other metals tested in inhibiting recA expression induced by hydrogen peroxide, xanthine oxidase, or the antibiotic ciprofloxacin. The close correlation between zinc’s effects on recA/SOS and on Stx suggested that inhibition of the SOS response is one mechanism by which zinc protects against STEC infection.ConclusionsZinc’s ability to protect against enteric bacterial pathogens may be the result of its combined effects on host tissues as well as inhibition of virulence in some pathogens. Research focused solely on the effects of zinc on pathogenic microbes may give an incomplete picture by failing to account for protective effects of zinc on host epithelia.

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Section: Discussionmentioning

confidence: 99%

Zinc protects against shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria

et al. 2014

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“…Furthermore, mice perfused with manganese became completely resistant to a lethal Shiga toxin challenge. Even though the results have not been replicated by another team [391], and caution is advised regarding its potential neurological toxicity, manganese deserves further clinical evaluation owing to its low cost.…”

Section: Manganesementioning

confidence: 99%

Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

Joseph

Cointe

Kurkdjian

et al. 2020

Toxins

155

132

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The severity of human infection by one of the many Shiga toxin-producing Escherichia coli (STEC) is determined by a number of factors: the bacterial genome, the capacity of human societies to prevent foodborne epidemics, the medical condition of infected patients (in particular their hydration status, often compromised by severe diarrhea), and by our capacity to devise new therapeutic approaches, most specifically to combat the bacterial virulence factors, as opposed to our current strategies that essentially aim to palliate organ deficiencies. The last major outbreak in 2011 in Germany, which killed more than 50 people in Europe, was evidence that an effective treatment was still lacking. Herein, we review the current knowledge of STEC virulence, how societies organize the prevention of human disease, and how physicians treat (and, hopefully, will treat) its potentially fatal complications. In particular, we focus on STEC-induced hemolytic and uremic syndrome (HUS), where the intrusion of toxins inside endothelial cells results in massive cell death, activation of the coagulation within capillaries, and eventually organ failure.

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“…Briefly, male CD-1 mice of 13 to 15 g, obtained from Charles River Laboratories (Wilmington, MA), were housed in filter-top cages with access to food and water ad libitum and challenged by intraperitoneal injection 3 days after arrival, as previously described (23). For partitioning studies, Stx2a was adjusted to deliver twice the mouse lethal dose (15 ng per mouse) in 0.5 ml phosphate-buffered saline (PBS) and then fractionated as described above.…”

Section: Methodsmentioning

confidence: 99%

AB ₅ Preassembly Is Not Required for Shiga Toxin Activity

et al. 2016

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Shiga toxin (Stx)-producing Escherichia coli (STEC) is a major cause of foodborne illness, including the life-threatening complication hemolytic-uremic syndrome. The German outbreak in 2011 resulted in nearly 4,000 cases of infection, with 54 deaths. Two forms of Stx, Stx1 and Stx2, differ in potency, and subtype Stx2a is most commonly associated with fatal human disease. Stx is considered to be an AB 5 toxin. The single A (enzymatically active) subunit inhibits protein synthesis by cleaving a catalytic adenine from the eukaryotic rRNA. The B (binding) subunit forms a homopentamer and mediates cellular association and toxin internalization by binding to the glycolipid globotriaosylceramide (Gb3). Both subunits are essential for toxicity. Here we report that unlike other AB 5 toxin family members, Stx is produced by STEC as unassembled A and B subunits. A preformed AB 5 complex is not required for cellular toxicity or in vivo toxicity to mice, and toxin assembly likely occurs at the cell membrane. We demonstrate that disruption of A-and B-subunit association by use of A-subunit peptides that lack enzymatic activity can protect mice from lethal doses of toxin. Currently, no treatments have been proven to be effective for hemolytic-uremic syndrome. Our studies demonstrate that agents that interfere with A-and B-subunit assembly may have therapeutic potential. Shiga toxin (Stx) produced by pathogenic Escherichia coli is considered to be an AB 5 heterohexamer; however, no known mechanisms ensure AB 5 assembly. Stx released by E. coli is not in the AB 5 conformation and assembles at the receptor interface. Thus, unassembled Stx can impart toxicity. This finding shows that preventing AB 5 assembly is a potential treatment for Stx-associated illnesses. IMPORTANCEComplications due to Shiga toxin are frequently fatal, and at present, supportive care is the only treatment option. Furthermore, antibiotic treatment is contraindicated due to the ability of antibiotics to amplify bacterial expression of Shiga toxin. We report, contrary to prevailing assumptions, that Shiga toxin produced by STEC circulates as unassembled A and B subunits at concentrations that are lethal to mice. Similar to the case for anthrax toxin, assembly occurs on receptors expressed on the surfaces of mammalian target cells. Disruption of Shiga toxin assembly by use of A-subunit peptides that lack enzymatic activity protects mice from lethal challenge with Shiga toxin, suggesting a new approach for development of therapeutics.

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Failure of Manganese to Protect from Shiga Toxin

Cited by 14 publications

References 30 publications

Zinc protects against shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria

Zinc protects against shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria

Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

AB ₅ Preassembly Is Not Required for Shiga Toxin Activity

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Failure of Manganese to Protect from Shiga Toxin

Cited by 14 publications

References 30 publications

Zinc protects against shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria

Zinc protects against shiga-toxigenic Escherichia coli by acting on host tissues as well as on bacteria

Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review

AB 5 Preassembly Is Not Required for Shiga Toxin Activity

Contact Info

Product

Resources

About

AB ₅ Preassembly Is Not Required for Shiga Toxin Activity