Differential tissue targeting and pathogenesis of verotoxins 1 and 2 in the mouse animal model

Rutjes, Niels W.; Binnington, Beth; Smith, Charles R.; Maloney, Mark; Lingwood, Clifford A.

doi:10.1046/j.1523-1755.2002.00502.x

Cited by 110 publications

(154 citation statements)

References 95 publications

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“…The Stx2/LPS-treated TM LeD/LeD mice also developed changes associated with thrombotic microangiopathic lesions in the brain and lung. These findings are consistent with those in humans with D+HUS and the fact that the Stx receptor Gb3 is expressed in the brain and lungs (46,47), and help to explain the reduced survival of the TM LeD/LeD mice. Our findings are rationale for determining whether TM gene variants in humans are associated with increased risk for the development of HUS upon STEC infection.…”

Section: Discussionsupporting

confidence: 88%

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Zoja

Locatelli

Pagani

et al. 2012

The Journal of Immunology

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Shiga toxin (Stx)-producing Escherichia coli is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The pathophysiology of renal microvascular thrombosis in Stx-HUS is still ill-defined. Based on evidence that abnormalities in thrombomodulin (TM), an anticoagulant endothelial glycoprotein that modulates complement and inflammation, predispose to atypical HUS, we assessed whether impaired TM function may adversely affect evolution of Stx-HUS. Disease was induced by coinjection of Stx2/LPS in wild-type mice (TMwt/wt) and mice that lack the lectin-like domain of TM (TMLeD/LeD), which is critical for its anti-inflammatory and cytoprotective properties. After Stx2/LPS, TMLeD/LeD mice exhibited more severe thrombocytopenia and renal dysfunction than TMwt/wt mice. Lack of lectin-like domain of TM resulted in a stronger inflammatory reaction after Stx2/LPS with more neutrophils and monocytes/macrophages infiltrating the kidney, associated with PECAM-1 and chemokine upregulation. After Stx2/LPS, intraglomerular fibrin(ogen) deposits were detected earlier in TMLeD/LeD than in TMwt/wt mice. More abundant fibrin(ogen) deposits were also found in brain and lungs. Under basal conditions, TMLeD/LeD mice exhibited excess glomerular C3 deposits, indicating impaired complement regulation in the kidney that could lead to local accumulation of proinflammatory products. TMLeD/LeD mice with HUS had a higher mortality rate than TMwt/wt mice. If applicable to humans, these findings raise the possibility that genetic or acquired TM defects might have an impact on the severity of microangiopathic lesions after exposure to Stx-producing E. coli infections and raise the potential for using soluble TM in the treatment of Stx-HUS.

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Section: Discussionsupporting

confidence: 88%

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Zoja

Locatelli

Pagani

et al. 2012

The Journal of Immunology

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“…For example, neurological damage is associated with HUS, and cerebral hemorrhage and edema have been reported in EHECinfected, streptomycin-pretreated mice (97,98). Although mice infected with C. rodentium (λstx 2dact ) occasionally displayed tremors and seizures, we did not observe consistent pathological changes in the nasal turbinates, a region of the CNS rich in the Stx receptor (79). In addition, contrary to what has been observed in human disease (6,8) and Stx administration models (47-49, 88, 99-101), mice infected with C. rodentium (λstx 2dact ) did not display renal platelet aggregation, red cell congestion, or fibrin deposition and did not show evidence of thrombocytopenia or anemia.…”

Section: Figurecontrasting

confidence: 80%

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

Mallick

McBee²,

Vanguri³

et al. 2012

J. Clin. Invest.

108

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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.

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“…In parallel, some mice were injected with Stx2 or LPS alone. Stx2 was chosen because it is associated with HUS clinical isolates more often than Stx1 (6) and because of the evidence that Stx2 injected in mice is more toxic and accumulates in the kidney to a greater extent than Stx1 (35).…”

Section: Experimental Model Of Husmentioning

confidence: 99%

Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

Morigi

Galbusera

Gastoldi

et al. 2011

The Journal of Immunology

209

195

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Shiga toxin (Stx)-producing E.coli O157:H7 has become a global threat to public health; it is a primary cause of diarrhea-associated hemolytic uremic syndrome (HUS), a disorder of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with thrombi occluding renal microcirculation. In this study, we explored whether Stx triggers complement-dependent microvascular thrombosis in in vitro and in vivo experimental settings of HUS. Stx induced on human microvascular endothelial cell surface the expression of P-selectin, which bound and activated C3 via the alternative pathway, leading to thrombus formation under flow. In the search for mechanisms linking complement activation and thrombosis, we found that exuberant complement activation in response to Stx generated an increased amount of C3a that caused further endothelial P-selectin expression, thrombomodulin (TM) loss, and thrombus formation. In a murine model of HUS obtained by coinjection of Stx2 and LPS and characterized by thrombocytopenia and renal dysfunction, upregulation of glomerular endothelial P-selectin was associated with C3 and fibrin(ogen) deposits, platelet clumps, and reduced TM expression. Treatment with anti–P-selectin Ab limited glomerular C3 accumulation. Factor B-deficient mice after Stx2/LPS exhibited less thrombocytopenia and were protected against glomerular abnormalities and renal function impairment, indicating the involvement of complement activation via the alternative pathway in the glomerular thrombotic process in HUS mice. The functional role of C3a was documented by data showing that glomerular fibrin(ogen), platelet clumps, and TM loss were markedly decreased in HUS mice receiving C3aR antagonist. These results identify Stx-induced complement activation, via P-selectin, as a key mechanism of C3a-dependent microvascular thrombosis in diarrhea-associated HUS.

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Differential tissue targeting and pathogenesis of verotoxins 1 and 2 in the mouse animal model

Abstract: The lung is a preferential (Gb(3)) "sink" for VT1, which explains the relatively slower clearance of VT2 and subsequent increased VT2 renal targeting and VT2 mortality in this animal model.

Cited by 110 publications

References 95 publications

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

Lack of the Lectin-like Domain of Thrombomodulin Worsens Shiga Toxin-Associated Hemolytic Uremic Syndrome in Mice

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

Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

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