Hemolytic uremic syndrome induced by lipopolysaccharide and Shiga-like toxin

Ikeda, Masahiro; Ito, Shuichi; Honda, Masashi

doi:10.1007/s00467-003-1395-7

Cited by 36 publications

(69 citation statements)

References 14 publications

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“…A few studies showed that there were consistent vascular or glomerular lesions (12,16,48), and the descriptions of these lesions varied between studies, confirming our findings that glomerular disease is present but mild in EHEC-infected mice. Several studies that used an injection model, in which Stx or Stx in combination with lipopolysaccharide was injected parenterally into mice, described glomerular lesions (11,13,15,20,45), supporting our finding that virulent EHEC is capable of inducing glomerular disease in mice.…”

Section: %)supporting

confidence: 89%

Pathogenesis of Renal Disease Due to Enterohemorrhagic Escherichia coli in Germ-Free Mice

et al. 2008

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Enterohemorrhagic Escherichia coli (EHEC) is a food-borne pathogen that causes hemorrhagic colitis and acute renal failure. We used a germ-free mouse model to investigate the role of host factors, Shiga toxin 2 (Stx2), and bacterial strain in disease due to EHEC. Germ-free male and female Swiss-Webster mice that were 3 days to 12 weeks old were orally inoculated with 1 of 10 EHEC strains or derivatives of two of these strains with Stx2 deleted. All inoculated mice became infected regardless of the inoculum dose. All bacterial strains colonized the intestines, reaching levels of 10 9 to 10 12 CFU/g of feces by 4 days after inoculation. Seven of the 10 wild-type strains caused disease. However, the two Stx2 deletion mutants, unlike the Stx2 ؉ parental strains, did not cause disease. The clinical signs of disease in mice included lethargy, dehydration, polyuria, polydypsia, and death. Postmortem examination of affected mice revealed dehydration and luminal cecal fluid accumulation. Histologic examination revealed close adherence of bacteria to the intestinal epithelium in the ileum and cecum but not in the colon. Other lesions included progressive renal tubular necrosis, glomerular fibrin thrombosis, and red blood cell sludging. The severity of disease varied according to the bacterial strain and age, but not sex, of the host. This study demonstrated that EHEC colonizes germ-free mice in large numbers, adheres to the intestinal epithelium, and causes luminal cecal fluid accumulation and progressive renal failure. The disease in mice was Stx2 and bacterial strain dependent. This animal model should be a useful tool for studying the pathogenesis of renal disease secondary to EHEC infection.Enterohemorrhagic Escherichia coli (EHEC), a food-borne bacterial pathogen of humans, is a normal inhabitant of the ruminant intestine. This organism is most often transmitted to humans in undercooked meat, but it has also caused outbreaks associated with contaminated vegetables (5, 28), fruit juices (6), and drinking water (41). The disease manifestations include watery or bloody diarrhea and can be severe enough to cause hospitalization and even death (18). In addition, some affected children (and rarely adults) develop hemolytic-uremic syndrome (HUS), a rapidly progressive, often fatal form of renal failure that is attributed to expression of Shiga toxins (Stx) by pathogenic bacteria (2, 18). HUS is defined by a triad of symptoms that includes hemolysis, uremia, and thrombocytopenia. It is a rare complication of disease due to EHEC, but its importance is amplified by its severity, tendency to affect young children, and the absence of any specific treatment or preventative measure. Thus, the significance of disease due to EHEC is derived from its food-borne nature and its potentially severe consequences.Both HUS and hemorrhagic colitis caused by EHEC have been attributed to the production of Stx by pathogenic bacteria (2, 50) referred to as Stx-producing E. coli (STEC). The Stxs are macromolecular cytotoxins that are phage encode...

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Section: %)supporting

confidence: 89%

Pathogenesis of Renal Disease Due to Enterohemorrhagic Escherichia coli in Germ-Free Mice

et al. 2008

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“…In a baboon model of HUS, LPS increased the toxicity of Stx (58). Consistently, both Stx2 and LPS were required to elicit a HUS-like response in mice (16,36,42). Our experiments document that in mice treated with Stx2/LPS that developed thrombocytopenia and renal failure, enhanced P-selectin expression on glomerular endothelial cells preceded C3 deposits.…”

Section: Discussionsupporting

confidence: 71%

“…The dosing protocol was based on previous studies (16,36). Mice were sacrificed at 3, 6, 24, or 48 h after injection.…”

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

214

201

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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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“…Therefore, the effects previously ascribed to Stx2 in murine podocytes may be due to a small contaminating dose of LPS. Furthermore, the murine glomerular endothelial cells displayed similar responses to LPS and insensitivity to Stx2, suggesting that murine models reporting glomerular damage are likely due to LPS or indirect effects of Stx2; only those models that use live STEC or inject mice with Shiga toxin plus LPS observe glomerular defects (13,28,33,59,63). Although the Stx2-induced HUS mouse model lacks glomerular damage, we believe this difference from human disease does not preclude the utility of this system.…”

Section: Vol 77 2009mentioning

confidence: 95%

“…Although multiple groups have been unable to locate the Shiga toxin receptor Gb 3 in glomeruli in murine renal sections (19,53), one group has reported that murine glomerular podocytes possess Gb 3 and respond to Stx2 in vitro (40), and another group has reported that renal tubular capillaries express the Gb 3 receptor (46). Furthermore, murine glomerular abnormalities, including platelet and fibrin deposition, occur in some murine HUS models (28,30,33,46,59,63). We demonstrate here that murine glomerular endothelial cells and podocytes are unresponsive to Stx2 because they do not produce the glycosphingolipid receptor Gb 3 in vitro or in vivo.…”

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confidence: 99%

Shiga Toxin 2 Targets the Murine Renal Collecting Duct Epithelium

et al. 2009

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Hemolytic-uremic syndrome (HUS) caused by Shiga toxin-producingEscherichia coli infection is a leading cause of pediatric acute renal failure. Bacterial toxins produced in the gut enter the circulation and cause a systemic toxemia and targeted cell damage. It had been previously shown that injection of Shiga toxin 2 (Stx2) and lipopolysaccharide (LPS) caused signs and symptoms of HUS in mice, but the mechanism leading to renal failure remained uncharacterized. The current study elucidated that murine cells of the glomerular filtration barrier were unresponsive to Stx2 because they lacked the receptor glycosphingolipid globotriaosylceramide (Gb 3 ) in vitro and in vivo. In contrast to the analogous human cells, Stx2 did not alter inflammatory kinase activity, cytokine release, or cell viability of the murine glomerular cells. However, murine renal cortical and medullary tubular cells expressed Gb 3 and responded to Stx2 by undergoing apoptosis. Stx2-induced loss of functioning collecting ducts in vivo caused production of increased dilute urine, resulted in dehydration, and contributed to renal failure. Stx2-mediated renal dysfunction was ameliorated by administration of the nonselective caspase inhibitor Q-VD-OPH in vivo. Stx2 therefore targets the murine collecting duct, and this Stx2-induced injury can be blocked by inhibitors of apoptosis in vivo.

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Hemolytic uremic syndrome induced by lipopolysaccharide and Shiga-like toxin

Cited by 36 publications

References 14 publications

Pathogenesis of Renal Disease Due to Enterohemorrhagic Escherichia coli in Germ-Free Mice

Pathogenesis of Renal Disease Due to Enterohemorrhagic Escherichia coli in Germ-Free Mice

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

Shiga Toxin 2 Targets the Murine Renal Collecting Duct Epithelium

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