Endothelial Binding of Beta Toxin to Small Intestinal Mucosal Endothelial Cells in Early Stages of Experimentally Induced Clostridium Perfringens Type C Enteritis in Pigs

Schumacher, Vanessa; Martel, An; Pasmans, Frank; Immerseel, Filip Van; Posthaus, Horst

doi:10.1177/0300985812461362

Cited by 26 publications

(30 citation statements)

References 12 publications

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“…Histologically, the hallmark of type C infection is necrosis of the intestinal wall, which starts in the mucosa but usually progresses to affect all layers of the intestine. Fibrin thrombi occluding superficial arteries and veins of the lamina propria and submucosa are characteristic of this condition (207), and it was postulated (although not yet definitely proven) that vascular damage by CPB is an early event in type C infections (211,212).…”

Section: Diseases Involving Primarily Plasmid-encoded Toxinsmentioning

confidence: 99%

Toxin Plasmids of Clostridium perfringens

Adams

Bannam

et al. 2013

Microbiol Mol Biol Rev

231

282

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SUMMARY In both humans and animals, Clostridium perfringens is an important cause of histotoxic infections and diseases originating in the intestines, such as enteritis and enterotoxemia. The virulence of this Gram-positive, anaerobic bacterium is heavily dependent upon its prolific toxin-producing ability. Many of the ∼16 toxins produced by C. perfringens are encoded by large plasmids that range in size from ∼45 kb to ∼140 kb. These plasmid-encoded toxins are often closely associated with mobile elements. A C. perfringens strain can carry up to three different toxin plasmids, with a single plasmid carrying up to three distinct toxin genes. Molecular Koch's postulate analyses have established the importance of several plasmid-encoded toxins when C. perfringens disease strains cause enteritis or enterotoxemias. Many toxin plasmids are closely related, suggesting a common evolutionary origin. In particular, most toxin plasmids and some antibiotic resistance plasmids of C. perfringens share an ∼35-kb region containing a Tn 916 -related conjugation locus named tcp (transfer of clostridial plasmids). This tcp locus can mediate highly efficient conjugative transfer of these toxin or resistance plasmids. For example, conjugative transfer of a toxin plasmid from an infecting strain to C. perfringens normal intestinal flora strains may help to amplify and prolong an infection. Therefore, the presence of toxin genes on conjugative plasmids, particularly in association with insertion sequences that may mobilize these toxin genes, likely provides C. perfringens with considerable virulence plasticity and adaptability when it causes diseases originating in the gastrointestinal tract.

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Section: Diseases Involving Primarily Plasmid-encoded Toxinsmentioning

confidence: 99%

Toxin Plasmids of Clostridium perfringens

Adams

Bannam

et al. 2013

Microbiol Mol Biol Rev

231

282

View full text Add to dashboard Cite

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“…The toxin forms pores in cells and in bilayer lipid membranes, creating channels that induce K + efflux and Ca 2+ , Na + and Cl − influxes, which are responsible for cell swelling and lysis (Nagahama et al, 2003). It has been shown to bind to intestinal endothelial cells, a fact that has been hypothesized to be an early step in endothelial cell necrosis, leading to thrombosis and ultimately intestinal necrosis (Miclard et al, 2009a and b; Schumacher et at, 2013). It has been recently demonstrated that CPB induces necrotic cell death in porcine endothelial cells in vitro, which is associated with an increase in intracellular calcium and is inhibited by necrostatin-1, suggesting a programmed cell necrosis (necroptosis) mechanism (Autheman et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…C. perfringens type C disease has been studied using several animal models including pigs, sheep, goats, rabbits, guinea pigs, and mice (Field and Goodwin, 1959; Kohler et al, 1979; Lawrence and Cooke, 1980; Johansen et al, 1986a,b,c; Sayeed et al, 2008; Uzal et al, 2009; Garcia et al, 2013; Schumacher et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

“…However, those experiments were performed using whole cultures or crude culture supernatants, and although the results confirmed that C. perfringens type C is a pathogen for piglets, they did not identify the main virulence factor(s) involved in the pathogenesis of those infections. The mechanism of action of CPB in type C infection was recently studied in intestinal loops of piglets (Schumacher et al, 2013). This study indicated that there is a tropism of CPB toward endothelial cells, suggesting that endothelial damage induced by CPB plays a role in the early stages of C. perfringens type C enteritis in pigs.…”

Section: Introductionmentioning

confidence: 99%

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Animal models to study the pathogenesis of human and animal Clostridium perfringens infections

Uzal

McClane

Cheung

et al. 2015

Veterinary Microbiology

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The most common animal models used to study Clostridium perfringens infections in humans and animals are reviewed here. The classical C. perfringens-mediated histotoxic disease of humans is clostridial myonecrosis or gas gangrene and the use of a mouse myonecrosis model coupled with genetic studies has contributed greatly to our understanding of disease pathogenesis. Similarly, the use of a chicken model has enhanced our understanding of type A-mediated necrotic enteritis in poultry and has led to the identification of NetB as the primary toxin involved in disease. C. perfringens type A food poisoning is a highly prevalent bacterial illness in the USA and elsewhere. Rabbits and mice are the species most commonly used to study the action of enterotoxin, the causative toxin. Other animal models used to study the effect of this toxin are rats, non-human primates, sheep and cattle. In rabbits and mice, CPE produces severe necrosis of the small intestinal epithelium along with fluid accumulation. C. perfringens type D infection has been studied by inoculating epsilon toxin (ETX) intravenously into mice, rats, sheep, goats and cattle, and by intraduodenal inoculation of whole cultures of this microorganism in mice, sheep, goats and cattle. Molecular Koch's postulates have been fulfilled for enterotoxigenic C. perfringens type A in rabbits and mice, for C. perfringens type A necrotic enteritis and gas gangrene in chickens and mice, respectively, for C. perfringens type C in mice, rabbits and goats, and for C. perfringens type D in mice, sheep and goats.

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“…In order to confirm that the endothelium is the target cell of perfringolysin or alpha toxin in bovine necrohemorrhagic enteritis, it would be interesting to localize the toxin in lesions, as already been done for beta toxin in necrotic enteritis in piglets and in a human case [31,32]. Beta toxin has been shown to induce porcine endothelial cell damage in vitro and to bind to endothelial cells, and not to epithelial cells, in the gut of diseased animals, suggesting that disruption of endothelial cells plays a role in type C enteritis [30,31,33]. …”

Section: Discussionmentioning

confidence: 99%

The synergistic necrohemorrhagic action of Clostridium perfringens perfringolysin and alpha toxin in the bovine intestine and against bovine endothelial cells

Verherstraeten

Goossens

Valgaeren

et al. 2013

Vet Res

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Bovine necrohemorrhagic enteritis is a major cause of mortality in veal calves. Clostridium perfringens is considered as the causative agent, but there has been controversy on the toxins responsible for the disease. Recently, it has been demonstrated that a variety of C. perfringens type A strains can induce necrohemorrhagic lesions in a calf intestinal loop assay. These results put forward alpha toxin and perfringolysin as potential causative toxins, since both are produced by all C. perfringens type A strains. The importance of perfringolysin in the pathogenesis of bovine necrohemorrhagic enteritis has not been studied before. Therefore, the objective of the current study was to evaluate the role of perfringolysin in the development of necrohemorrhagic enteritis lesions in calves and its synergism with alpha toxin. A perfringolysin-deficient mutant, an alpha toxin-deficient mutant and a perfringolysin alpha toxin double mutant were less able to induce necrosis in a calf intestinal loop assay as compared to the wild-type strain. Only complementation with both toxins could restore the activity to that of the wild-type. In addition, perfringolysin and alpha toxin had a synergistic cytotoxic effect on bovine endothelial cells. This endothelial cell damage potentially explains why capillary hemorrhages are an initial step in the development of bovine necrohemorrhagic enteritis. Taken together, our results show that perfringolysin acts synergistically with alpha toxin in the development of necrohemorrhagic enteritis in a calf intestinal loop model and we hypothesize that both toxins act by targeting the endothelial cells.

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Endothelial Binding of Beta Toxin to Small Intestinal Mucosal Endothelial Cells in Early Stages of Experimentally Induced Clostridium Perfringens Type C Enteritis in Pigs

Cited by 26 publications

References 12 publications

Toxin Plasmids of Clostridium perfringens

Toxin Plasmids of Clostridium perfringens

Animal models to study the pathogenesis of human and animal Clostridium perfringens infections

The synergistic necrohemorrhagic action of Clostridium perfringens perfringolysin and alpha toxin in the bovine intestine and against bovine endothelial cells

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