Evidence for cytoskeletal changes secondary to plasma membrane functional alterations in the in vitro cell response to Clostridium perfringens epsilon-toxin

Donelli, Gianfranco; Fiorentini, Carla; Matarrese, Paola; Falzano, Loredana; Cardines, Rita; Mastrantonio, Paola; Payne, Dean; Titball, Richard W.

doi:10.1016/s0147-9571(02)00052-8

Cited by 15 publications

(8 citation statements)

References 32 publications

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“…In addition to altering the membrane, secondary effects of epsilon intoxication involve cytoskeletal dysfunction [51] affecting integrity of cell monolayers [42]. Disruption of cell monolayers provides further understanding of the subsequent dysfunction of vascular endothelium, edema and crossing of the blood-brain barrier by the toxin as well as albumin-sized (~65 kDa) molecules [52,53].…”

Section: Epsilon Toxin (Etx): C Perfringens Most Toxic Toxinmentioning

confidence: 99%

Clostridium perfringens Epsilon Toxin: A Malevolent Molecule for Animals and Man?

Stiles

Barth

et al. 2013

Toxins

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Clostridium perfringens is a prolific, toxin-producing anaerobe causing multiple diseases in humans and animals. One of these toxins is epsilon, a 33 kDa protein produced by Clostridium perfringens (types B and D) that induces fatal enteric disease of goats, sheep and cattle. Epsilon toxin (Etx) belongs to the aerolysin-like toxin family. It contains three distinct domains, is proteolytically-activated and forms oligomeric pores on cell surfaces via a lipid raft-associated protein(s). Vaccination controls Etx-induced disease in the field. However, therapeutic measures are currently lacking. This review initially introduces C. perfringens toxins, subsequently focusing upon the Etx and its biochemistry, disease characteristics in various animals that include laboratory models (in vitro and in vivo), and finally control mechanisms (vaccines and therapeutics).

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Section: Epsilon Toxin (Etx): C Perfringens Most Toxic Toxinmentioning

confidence: 99%

Clostridium perfringens Epsilon Toxin: A Malevolent Molecule for Animals and Man?

Stiles

Barth

et al. 2013

Toxins

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“…Many bacterial toxins, such as Clostridium difficile toxins A and B, Escherichia coli cytotoxic necrotizing factor 1 (CNF1) and others (Aktories and Barbieri, 2005), produce actin changes, but no one of them has been reported to stabilize microtubules (MTs) to the extent and speed shown here for PLY (Fiorentini et al ., 2003). The Clostridium perfringens ε‐toxin can produce MT entanglement, but in a receptor‐dependent manner and in a limited number of cell types such as MDCK cells (Donelli et al ., 2003). Furthermore, the ε‐toxin requires proteolytic processing to attain activity (Cole et al ., 2004).…”

Section: Introductionmentioning

confidence: 99%

Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol‐dependent, non‐lytic and Src‐kinase dependent manner inhibits intracellular trafficking

Iliev

Djannatian

Opazo

et al. 2009

Molecular Microbiology

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SummaryStreptococcus pneumoniae is the most frequent cause of bacterial meningitis, leading to permanent neurological damage in 30% and lethal outcome in 25% of patients. The cholesterol-dependent cytolysin pneumolysin is a major virulence factor of S. pneumoniae. It produces rapid cell lysis at higher concentrations or apoptosis at lower concentrations. Here, we show that sublytic amounts of pneumolysin produce rapid bundling and increased acetylation of microtubules (signs of excessive microtubule stabilization) in various types of cells -neuroblastoma cells, fibroblasts and primary astrocytes. The bundling started perinuclearly and extended peripherally towards the membrane. The effect was not connected to pneumolysin's capacity to mediate calcium influx, macropore formation, apoptosis, or RhoA and Rac1 activation. Cellular cholesterol depletion and neutralization of the toxin by pre-incubation with cholesterol completely inhibited the microtubule phenotype. Pharmacological inhibition of Src-family kinases diminished microtubule bundling, suggesting their involvement in the process. The relevance of microtubule stabilization to meningitis was confirmed in an experimental pneumococcal meningitis animal model, where increased acetylation was observed. Live imaging experiments demonstrated a decrease in organelle motility after toxin challenge in a manner comparable to the microtubule-stabilizing agent taxol, thus proposing a possible pathogenic mechanism that might contribute to the CNS damage in pneumococcal meningitis.

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“…Intoxicated cells undergo morphological changes including swelling and formation of membrane blebs [33]. The rapid death of cells exposed to the toxin [34] results in the formation of a large membrane complex on the target cell surface [33], leading to pore formation, an efflux of K + and an influx of Na + and Cl − ions [35]. In addition, cytotoxicity is temperature‐ and pH‐dependent [36] and is potentiated by EDTA [37].…”

Section: Effects Of ε‐Toxin On Cultured Cellsmentioning

confidence: 99%

Molecular basis of toxicity of Clostridium perfringens epsilon toxin

et al. 2011

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Clostridium perfringensε‐toxin is produced by toxinotypes B and D strains. The toxin is the aetiological agent of dysentery in newborn lambs but is also associated with enteritis and enterotoxaemia in goats, calves and foals. It is considered to be a potential biowarfare or bioterrorism agent by the US Government Centers for Disease Control and Prevention. The relatively inactive 32.9 kDa prototoxin is converted to active mature toxin by proteolytic cleavage, either by digestive proteases of the host, such as trypsin and chymotrypsin, or by C. perfringensλ‐protease. In vivo, the toxin appears to target the brain and kidneys, but relatively few cell lines are susceptible to the toxin, and most work has been carried out using Madin–Darby canine kidney (MDCK) cells. The binding of ε‐toxin to MDCK cells and rat synaptosomal membranes is associated with the formation of a stable, high molecular weight complex. The crystal structure of ε‐toxin reveals similarity to aerolysin from Aeromonas hydrophila, parasporin‐2 from Bacillus thuringiensis and a lectin from Laetiporus sulphureus. Like these toxins, ε‐toxin appears to form heptameric pores in target cell membranes. The exquisite specificity of the toxin for specific cell types suggests that it binds to a receptor found only on these cells.

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Evidence for cytoskeletal changes secondary to plasma membrane functional alterations in the in vitro cell response to Clostridium perfringens epsilon-toxin

Cited by 15 publications

References 32 publications

Clostridium perfringens Epsilon Toxin: A Malevolent Molecule for Animals and Man?

Clostridium perfringens Epsilon Toxin: A Malevolent Molecule for Animals and Man?

Rapid microtubule bundling and stabilization by the Streptococcus pneumoniae neurotoxin pneumolysin in a cholesterol‐dependent, non‐lytic and Src‐kinase dependent manner inhibits intracellular trafficking

Molecular basis of toxicity of Clostridium perfringens epsilon toxin

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