Evidence that Clostridium perfringens Enterotoxin-Induced Intestinal Damage and Enterotoxemic Death in Mice Can Occur Independently of Intestinal Caspase-3 Activation

Freedman, John C.; Navarro, Mauricio A.; Morrell, Eleonora; Beingesser, Juliann; Shrestha, Archana; McClane, Bruce A.; Uzal, Francisco A.

doi:10.1128/iai.00931-17

Cited by 12 publications

(18 citation statements)

References 26 publications

(44 reference statements)

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“…In contrast to the in vitro findings previously commented, treatment of mice intestinal loops with CPE induced a dose- and time- dependent caspase-3 activation [ 153 ]. This activation, however, was not essential for the development of intestinal lesions, because the use of the pan-caspase inhibitor Q-VD-OPh did not protect from intestinal damage or enterotoxemic death [ 153 ]. The role of calpain activation and a potential involvement of necroptosis in CPE-associated disease have not been explored.…”

Section: C Perfringens Enterotoxin (Cpe)contrasting

confidence: 64%

Mechanisms of Action and Cell Death Associated with Clostridium perfringens Toxins

Navarro

McClane

Uzal

2018

Toxins

161

114

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Clostridium perfringens uses its large arsenal of protein toxins to produce histotoxic, neurologic and intestinal infections in humans and animals. The major toxins involved in diseases are alpha (CPA), beta (CPB), epsilon (ETX), iota (ITX), enterotoxin (CPE), and necrotic B-like (NetB) toxins. CPA is the main virulence factor involved in gas gangrene in humans, whereas its role in animal diseases is limited and controversial. CPB is responsible for necrotizing enteritis and enterotoxemia, mostly in neonatal individuals of many animal species, including humans. ETX is the main toxin involved in enterotoxemia of sheep and goats. ITX has been implicated in cases of enteritis in rabbits and other animal species; however, its specific role in causing disease has not been proved. CPE is responsible for human food-poisoning and non-foodborne C. perfringens-mediated diarrhea. NetB is the cause of necrotic enteritis in chickens. In most cases, host–toxin interaction starts on the plasma membrane of target cells via specific receptors, resulting in the activation of intracellular pathways with a variety of effects, commonly including cell death. In general, the molecular mechanisms of cell death associated with C. perfringens toxins involve features of apoptosis, necrosis and/or necroptosis.

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Section: C Perfringens Enterotoxin (Cpe)contrasting

confidence: 64%

Mechanisms of Action and Cell Death Associated with Clostridium perfringens Toxins

Navarro

McClane

Uzal

2018

Toxins

161

114

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“…This protection did not involve mepacrine inactivating the CPE protein; instead, this drug interfered with the formation of CPE pores and with the activity of pores already present on CPE-treated Caco-2 cells (31). With this previous information, the present study evaluated the potential therapeutic role of mepacrine against CPE in vivo using a mouse intestinal loop model of severe CPE action, which reproduces CPE-induced intestinal damage and enterotoxemic death in these animals (9,10).…”

Section: Discussionmentioning

confidence: 95%

“…Mepacrine protects mice from enterotoxemic death caused by CPE. As mentioned in the Introduction, CPE is thought to cause fatal enterotoxemia after being absorbed from the intestine in individuals with severe constipation or fecal impaction, conditions that prolong contact between the toxin and the intestinal mucosa, thereby facilitating CPE absorption into the blood to damage distant organs (6,(8)(9)(10). Therefore, we evaluated whether mepacrine can protect mice from enterotoxemic death caused by CPE.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we evaluated whether mepacrine can protect mice from enterotoxemic death caused by CPE. In this experiment, mouse intestinal loops were cotreated for a prolonged period (up to 4 h) with 1 ml of Hank's balanced salt solution (HBSS) containing 100 g of CPE (a dose known to cause enterotoxemia [9,10]) and one of two concentrations of mepacrine (0.5 or 1.0 mM). When viability was monitored, all mice (100%) treated with mepacrine alone (no CPE) survived for the full 4-h experimental period.…”

Section: Resultsmentioning

confidence: 99%

“…␤-Hairpin loops from the N-terminal domain of CPE extend to form a ␤-barrel, which inserts into the lipid bilayer to create a pore (22). The resulting CPE oligomeric pore, named the CH-1 large complex, is cation permeable and creates a Ca 2ϩ influx into cells that triggers cell death (10,(23)(24)(25)(26)(27)(28).…”

mentioning

confidence: 99%

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Potential Therapeutic Effects of Mepacrine against Clostridium perfringens Enterotoxin in a Mouse Model of Enterotoxemia

et al. 2019

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Clostridium perfringens enterotoxin (CPE) is a pore-forming toxin that causes the symptoms of common bacterial food poisoning and several non-foodborne human gastrointestinal diseases, including antibiotic-associated diarrhea and sporadic diarrhea. In some cases, CPE-mediated disease can be very severe or fatal due to the involvement of enterotoxemia. Therefore, the development of potential therapeutics against CPE action during enterotoxemia is warranted. Mepacrine, an acridine derivative drug with broad-spectrum effects on pores and channels in mammalian membranes, has been used to treat protozoal intestinal infections in human patients. A previous study showed that the presence of mepacrine inhibits CPE-induced pore formation and activity in enterocyte-like Caco-2 cells, reducing the cytotoxicity caused by this toxin in vitro. Whether mepacrine is similarly protective against CPE action in vivo has not been tested. When the current study evaluated whether mepacrine protects against CPEinduced death and intestinal damage using a murine ligated intestinal loop model, mepacrine protected mice from the enterotoxemic lethality caused by CPE. This protection was accompanied by a reduction in the severity of intestinal lesions induced by the toxin. Mepacrine did not reduce CPE pore formation in the intestine but inhibited absorption of the toxin into the blood of some mice. Protection from enterotoxemic death correlated with the ability of this drug to reduce CPE-induced hyperpotassemia. These in vivo findings, coupled with previous in vitro studies, support mepacrine as a potential therapeutic against CPE-mediated enterotoxemic disease.

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Comparative pathogenesis of enteric clostridial infections in humans and animals

Uzal

Navarro

et al. 2018

Anaerobe

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Several enteric clostridial diseases can affect humans and animals. Of these, the enteric infections caused by Clostridium perfringens and Clostridium difficile are amongst the most prevalent and they are reviewed here. C. perfringens type A strains encoding alpha toxin (CPA) are frequently associated with enteric disease of many animal mammalian species, but their role in these diseased mammals remains to be clarified. C. perfringens type B encoding CPA, beta (CPB) and epsilon (ETX) toxins causes necro-hemorrhagic enteritis, mostly in sheep, and these strains have been recently suggested to be involved in multiple sclerosis in humans, although evidence of this involvement is lacking. C. perfringens type C strains encode CPA and CPB and cause necrotizing enteritis in humans and animals, while CPA and ETX producing type D strains of C. perfringens produce enterotoxemia in sheep, goats and cattle, but are not known to cause spontaneous disease in humans. The role of C. perfringens type E in animal or human disease remains poorly defined. The newly revised toxinotype F encodes CPA and enterotoxin (CPE), the latter being responsible for food poisoning in humans, and the less prevalent antibiotic associated and sporadic diarrhea. The role of these strains in animal disease has not been fully described and remains controversial. Another newly created toxinotype, G, encodes CPA and necrotic enteritis toxin B-like (NetB), and is responsible for avian necrotic enteritis, but has not been associated with human disease. C. difficile produces colitis and/or enterocolitis in humans and multiple animal species. The main virulence factors of this microorganism are toxins A, B and an ADP-ribosyltransferase (CDT). Other clostridia causing enteric diseases in humans and/or animals are Clostridium spiroforme, Clostridium piliforme, Clostridium colinum, Clostridium sordellii, Clostridium chauvoei, Clostridium septicum, Clostridium botulinum, Clostridium butyricum and Clostridium neonatale. The zoonotic transmission of some, but not all these clostridsial species, has been demonstrated.

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Evidence that Clostridium perfringens Enterotoxin-Induced Intestinal Damage and Enterotoxemic Death in Mice Can Occur Independently of Intestinal Caspase-3 Activation

Cited by 12 publications

References 26 publications

Mechanisms of Action and Cell Death Associated with Clostridium perfringens Toxins

Mechanisms of Action and Cell Death Associated with Clostridium perfringens Toxins

Potential Therapeutic Effects of Mepacrine against Clostridium perfringens Enterotoxin in a Mouse Model of Enterotoxemia

Comparative pathogenesis of enteric clostridial infections in humans and animals

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