Pathogenic Mechanism of Mouse Brain Damage Caused by Oral Infection with Shiga Toxin-Producing<i>Escherichia coli</i>O157:H7

Kita, Eisuke; Yunou, Yoshihisa; Kurioka, Takaaki; Harada, Hiroko; Yoshikawa, Shinji; Mikasa, Keiichi; Higashi, Nobutaka

doi:10.1128/iai.68.3.1207-1214.2000

Cited by 41 publications

(41 citation statements)

References 41 publications

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“…These results support the notion that PRBC-mediated stimulation of endothelial cells is incomplete and promotes parasite sequestration in the peripheral vascular bed rather than triggering local inflammation, which requires leukocyte adhesion to activated endothelial cells. Endothelial responsiveness to TNF-␣ has been shown to be a determinant of pathology during infections with a number of pathogens (7,13,14,24,25). It is intriguing to speculate that development of partial anergy towards stimulation by the paracrine TNF-␣ as a result of continuous exposure to PRBC contributes to the absence of immune pathology and clinical disease during chronic malaria infection, which is observed in individuals living in areas with a high prevalence of infected mosquitoes who have a high burden of circulating parasites.…”

Section: Discussionmentioning

confidence: 99%

Direct Activation of Human Endothelial Cells by Plasmodium falciparum -Infected Erythrocytes

et al. 2005

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Section: Discussionmentioning

confidence: 99%

Direct Activation of Human Endothelial Cells by Plasmodium falciparum -Infected Erythrocytes

et al. 2005

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“…3b). Considering the close relationship between Stx-caused vascular damage in the central nervous system and its mortality in mice (3,19,23,24), these results suggest that SUPER TWIG (1)6 suppressed the lethality of Stx2 by diminishing the deposition of Stx2 in the brain and the subsequent fatal damage.…”

Section: Super Twigs (1)6 and (1)12 Directly Bind To The Stx B Subunimentioning

confidence: 99%

“…Stx2 causes multifocal vascular damage in the central nervous system, which is closely related to its morbidity and mortality in animal models (3,18,19,(22)(23)(24). Therefore, pathological changes in cerebral blood vessels, such as congestion and hemorrhage, were investigated after the i.v.…”

Section: Super Twigs (1)6 and (1)12 Directly Bind To The Stx B Subunimentioning

confidence: 99%

“…Furthermore, in the physiological scenario SUPER TWIG (1)6 protected mice from challenge with a fatal dose of E. coli O157:H7, even when administered after the establishment of the infection. Therapeutically, this type of neutralizer is expected to have superior advantages to prevent the progression of the life-threatening systemic complications caused by STEC infection, because recent highly sensitive Stxdetection systems make it possible to diagnose the establishment of these infections at a very early stage (4,19,24). Also SUPER TWIG (1)6 functions in vivo by a unique dual mechanism: (i) it binds to Stx with high affinity and inhibits its Gb 3 -dependent incorporation into target cells; (ii) it induces active uptake and subsequent degradation of Stx by macrophages present in the reticuloendothelium.…”

Section: Super Twigs (1)6 and (1)12 Directly Bind To The Stx B Subunimentioning

confidence: 99%

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A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7

Nishikawa

Matsuoka

Kita

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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189

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Infection with Shiga toxin (Stx)-producing Escherichia coli O157:H7, which causes diarrhea and hemorrhagic colitis in humans, often results in fatal systemic complications, such as neurological damage and hemolytic-uremic syndrome. Because Stx circulating in the blood is a major causative factor of these complications, the development of a Stx neutralizer that functions in the circulation holds promise as a viable therapy. Here we developed a series of carbosilane dendrimers, in which trisaccharides of globotriaosyl ceramide, a receptor for Stx, were variously oriented at their termini (referred to as SUPER TWIG), and identified a SUPER TWIG with six trisaccharides as a Stx neutralizer functioning in the circulation. This SUPER TWIG specifically bound to Stx with high affinity (Kd ‫؍‬ 1.1 ؋ 10 ؊6 M) and inhibited the incorporation of the toxin into target cells. Intravenous administration of the SUPER TWIG along with Stx to mice substantially reduced the fatal brain damage and completely suppressed the lethal effect of Stx. Moreover, the SUPER TWIG protected mice from challenge with a fatal dose of E. coli O157:H7, even when administered after the establishment of the infection. The SUPER TWIG neutralized Stx in vivo by a mechanism in which the accumulation and immediate degradation of Stx by phagocytic macrophages present in the reticuloendothelial system were induced. Taken together, our findings indicate that this SUPER TWIG is therapeutic agent against infections by Stx-producing E. coli.

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“…Accumulating data from animal models and epidemiological studies have linked the family of Shiga toxins (Stx), produced by these strains, to the development of neurologic disturbances (4,8,9,10,12,19). However, the Shiga toxins are not classical neurotoxins.…”

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Bidirectional Concentration-Dependent Effects of Tumor Necrosis Factor Alpha in Shigella dysenteriae -Related Seizures

2003

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We have previously demonstrated that pretreatment of mice with Shigella dysenteriae sonicate enhanced their susceptibility to pentylenetetrazole-induced seizures and that tumor necrosis factor alpha (TNF-␣) was proconvulsive in this respect. The present study shows that TNF-␣, at high concentrations, may also exert a suppressive effect on Shigella-mediated seizures. This implies that high levels of TNF-␣ may play a protective role in neurologic complications of S. dysenteriae infection.The acute gastrointestinal infections caused by Shigella dysenteriae and enterohemorrhagic Escherichia coli (EHEC) strains are often accompanied by neurologic disturbances, mainly convulsions and encephalopathy (2,5,9).The pathogenesis of the neurologic manifestations in shigellosis and EHEC infections is as yet unclear. Accumulating data from animal models and epidemiological studies have linked the family of Shiga toxins (Stx), produced by these strains, to the development of neurologic disturbances (4,8,9,10,12,19). However, the Shiga toxins are not classical neurotoxins. It is assumed that their neurotoxicity stems primarily from their ability to inflict cytotoxic damage on the microvascular endothelium of the central nervous system (CNS).The infections caused by S. dysenteriae and EHEC cause a severe inflammation of the bowel which is triggered by extensive production of proinflammatory cytokines (15,28). An increase in tumor necrosis factor alpha (TNF-␣) and interleukin-1␤ (IL-1␤) has been found in the stool and plasma of patients with acute shigellosis, and the increased levels correlated with the clinical severity of the intestinal disease (18).Recently, our group has developed an animal model to investigate Shigella-related seizures. Administration of the proconvulsant pentylenetetrazole (PTZ) to mice induces clonictonic seizures within minutes of its application, owing to its antagonistic activity at the benzodiazepine/␥-aminobutyric acid receptor complex. Using this model, we found that pretreatment of mice with crude preparations of S. dysenteriae or E. coli H-30 significantly increased their response to PTZ-induced seizures (27). The increased response could be mimicked by coadministration of Shiga toxin and lipopolysaccharide. In the same model, we also demonstrated that TNF-␣, IL-1␤, and nitric oxide (NO) play an important role in the sensitization of the CNS to convulsive activity (3,26).In the course of these experiments, we noted that pretreatment of mice with high concentrations of S. dysenteriae sonicate was less effective than pretreatment with lower concentrations and sometimes failed completely to enhance the response to PTZ. We hypothesized that, in high concentrations, mediators induced by Shigella sonicate may have an inhibitory effect on enhancement of seizures. This was supported by evidence that cytokines, and specifically TNF-␣, may exert dual effects in the CNS (20, 23). The aim of the present study was to investigate the concentration-dependent effects of TNF-␣ in Shigella-related seizures.Pretreatm...

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Pathogenic Mechanism of Mouse Brain Damage Caused by Oral Infection with Shiga Toxin-ProducingEscherichia coliO157:H7

Cited by 41 publications

References 41 publications

Direct Activation of Human Endothelial Cells by Plasmodium falciparum -Infected Erythrocytes

Direct Activation of Human Endothelial Cells by Plasmodium falciparum -Infected Erythrocytes

A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7

Bidirectional Concentration-Dependent Effects of Tumor Necrosis Factor Alpha in Shigella dysenteriae -Related Seizures

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