Mouse Model of Hemolytic-Uremic Syndrome Caused by Endotoxin-Free Shiga Toxin 2 (Stx2) and Protection from Lethal Outcome by Anti-Stx2 Antibody

Sauter, Kristin A.; Melton‐Celsa, Angela R.; Larkin, Kay; Troxell, Megan L.; O'Brien, Alison D.; Magun, Bruce E.

doi:10.1128/iai.00592-08

Cited by 74 publications

(85 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast, mortality was observed in mice infected with C. rodentium (λstx 2dact ) starting at day 4 after infection, and (in the experiment represented in Figure 2D) no mice survived past day 9. Consistent with the previous correlation between weight loss and serious systemic disease (47,48,54), nearly all (~95%) of mice that died or were euthanized had lost >20% body weight at the preceding weight assessment (data not shown).…”

Section: Stx-mediated Systemic Induction Of Proinflammatory Cytokinessupporting

confidence: 74%

“…Weight loss is a notable feature in mice after Stx injection or infection in mice with an intact commensal flora with high doses of STEC (47,48,54). We found that mock-infected mice, as well as mice infected with C. rodentium DBS100 or C. rodentium (λstx 2dact ::kan R ), maintained body weight throughout infection, indicating that infection with C. rodentium strains that do not produce Stx were not associated with weight loss ( Figure 2C).…”

Section: Figurementioning

confidence: 65%

“…Instead, in measuring 23 cytokines in the sera of mice infected with C. rodentium (λstx 2dact ) at 7-10 days after infection (see Methods), we found that several proinflammatory cytokines and chemokines commonly associated with disease in humans and animal models of HUS (47,48,50,(76)(77)(78) were elevated relative to those in mock-infected mice and mice infected with C. rodentium (λstx 2dact ::kan R ). Serum levels of the proinflammatory cytokine TNF-α were elevated, as were the neutrophil chemoattractants IL-17 and KC ( Figure 4).…”

Section: Stx-mediated Systemic Induction Of Proinflammatory Cytokinesmentioning

confidence: 99%

“…Injection of Stx into mice results in the induction of proinflammatory cytokines, vascular damage, hemolysis, and renal damage (47)(48)(49)(50), but in contrast to piglet and rabbit infection models (23, 51-53), STEC strain originally isolated from ground beef (66). In preliminary screening of these C. rodentium lysogens, only C. rodentium (Φ1720a-02) produced significant amounts of toxin in vitro or caused systemic disease in mice (data not shown; see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A novel murine infection model for Shiga toxin–producing Escherichia coli

Mallick

McBee²,

Vanguri³

et al. 2012

J. Clin. Invest.

Self Cite

118

View full text Add to dashboard Cite

Enterohemorrhagic E. coli (EHEC) is an important subset of Shiga toxin-producing (Stx-producing) E. coli (STEC), pathogens that have been implicated in outbreaks of food-borne illness and can cause intestinal and systemic disease, including severe renal damage. Upon attachment to intestinal epithelium, EHEC generates "attaching and effacing" (AE) lesions characterized by intimate attachment and actin rearrangement upon host cell binding. Stx produced in the gut transverses the intestinal epithelium, causing vascular damage that leads to systemic disease. Models of EHEC infection in conventional mice do not manifest key features of disease, such as AE lesions, intestinal damage, and systemic illness. In order to develop an infection model that better reflects the pathogenesis of this subset of STEC, we constructed an Stx-producing strain of Citrobacter rodentium, a murine AE pathogen that otherwise lacks Stx. Mice infected with Stx-producing C. rodentium developed AE lesions on the intestinal epithelium and Stx-dependent intestinal inflammatory damage. Further, the mice experienced lethal infection characterized by histopathological and functional kidney damage. The development of a murine model that encompasses AE lesion formation and Stx-mediated tissue damage will provide a new platform upon which to identify EHEC alterations of host epithelium that contribute to systemic disease.

show abstract

Section: Stx-mediated Systemic Induction Of Proinflammatory Cytokinessupporting

confidence: 74%

Section: Figurementioning

confidence: 65%

Section: Stx-mediated Systemic Induction Of Proinflammatory Cytokinesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A novel murine infection model for Shiga toxin–producing Escherichia coli

Mallick

McBee²,

Vanguri³

et al. 2012

J. Clin. Invest.

Self Cite

118

View full text Add to dashboard Cite

show abstract

“…Mice injected with this dose of Stx2 usually develop symptoms after 3-4 days. 4,28 Mice were euthanized before symptoms developed in order to detect early apoptotic changes.…”

Section: Ouabain Protects Kidneys From Apoptosis In Stx2-treated Micementioning

confidence: 99%

Ouabain Protects against Shiga Toxin–Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL

Burlaka

Liu

Rebetz

et al. 2013

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Hemolytic uremic syndrome, a life-threatening disease often accompanied by acute renal failure, usually occurs after gastrointestinal infection with Shiga toxin 2 (Stx2)-producing Escherichia coli. Stx2 binds to the glycosphingolipid globotriaosylceramide receptor, expressed by renal epithelial cells, and triggers apoptosis by activating the apoptotic factor Bax. Signaling via the ouabain/Na,K-ATPase/IP3R/NF-kB pathway increases expression of Bcl-xL, an inhibitor of Bax, suggesting that ouabain might protect renal cells from Stx2-triggered apoptosis. Here, exposing rat proximal tubular cells to Stx2 in vitro resulted in massive apoptosis, upregulation of the apoptotic factor Bax, increased cleaved caspase-3, and downregulation of the survival factor Bcl-xL; co-incubation with ouabain prevented all of these effects. Ouabain activated the NF-kB antiapoptotic subunit p65, and the inhibition of p65 DNA binding abolished the antiapoptotic effect of ouabain in Stx2-exposed tubular cells. Furthermore, in vivo, administration of ouabain reversed the imbalance between Bax and Bcl-xL in Stx2-treated mice. Taken together, these results suggest that ouabain can protect the kidney from the apoptotic effects of Stx2.

show abstract

Direct acute tubular damage contributes to Shigatoxin‐mediated kidney failure

Porubský

Federico

Müthing

et al. 2014

The Journal of Pathology

View full text Add to dashboard Cite

The pathogenesis and therapy of Shigatoxin 2 (Stx2)-mediated kidney failure remain controversial. Our aim was to test whether, during an infection with Stx2-producing E. coli (STEC), Stx2 exerts direct effects on renal tubular epithelium and thereby possibly contributes to acute renal failure. Mice represent a suitable model because they, like humans, express the Stx2-receptor Gb3 in the tubular epithelium but, in contrast to humans, not in glomerular endothelia, and are thus free of glomerular thrombotic microangiopathy (TMA). In wild-type mice, Stx2 caused acute tubular dysfunction with consequent electrolyte disturbance, which was most likely the cause of death. Tubule-specific depletion of Gb3 protected the mice from acute renal failure. In vitro, Stx2 induced secretion of proinflammatory cytokines and apoptosis in human tubular epithelial cells, thus implicating a direct effect of Stx2 on the tubular epithelium. To correlate these results to human disease, kidney biopsies and outcome were analysed in patients with Stx2-associated kidney failure (n = 11, aged 22–44 years). The majority of kidney biopsies showed different stages of an ongoing TMA; however, no glomerular complement activation could be demonstrated. All biopsies, including those without TMA, showed severe acute tubular damage. Due to these findings, patients were treated with supportive therapy without complement-inhibiting antibodies (eculizumab) or immunoadsorption. Despite the severity of the initial disease [creatinine 6.34 (1.31–17.60) mg/dl, lactate dehydrogenase 1944 (753–2792) U/l, platelets 33 (19–124)/nl and haemoglobin 6.2 (5.2–7.8) g/dl; median (range)], all patients were discharged after 33 (range 19–43) days with no neurological symptoms and no dialysis requirement [creatinine 1.39 (range 0.84–2.86) mg/dl]. The creatinine decreased further to 0.90 (range 0.66–1.27) mg/dl after 24 months. Based on these data, one may surmise that acute tubular damage represents a separate pathophysiological mechanism, importantly contributing to Stx2-mediated acute kidney failure. Specifically in young adults, an excellent outcome can be achieved by supportive therapy only. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

show abstract

Mouse Model of Hemolytic-Uremic Syndrome Caused by Endotoxin-Free Shiga Toxin 2 (Stx2) and Protection from Lethal Outcome by Anti-Stx2 Antibody

Cited by 74 publications

References 62 publications

A novel murine infection model for Shiga toxin–producing Escherichia coli

A novel murine infection model for Shiga toxin–producing Escherichia coli

Ouabain Protects against Shiga Toxin–Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL

Direct acute tubular damage contributes to Shigatoxin‐mediated kidney failure

Contact Info

Product

Resources

About