Epsilon toxin: a fascinating pore‐forming toxin

Abstract

Epsilon toxin (ETX) is produced by strains of Clostridium perfringens classified as type B or type D. ETX belongs to the heptameric β‐pore‐forming toxins including aerolysin and Clostridium septicum alpha toxin, which are characterized by the formation of a pore through the plasma membrane of eukaryotic cells consisting in a β‐barrel of 14 amphipatic β strands. By contrast to aerolysin and C. septicum alpha toxin, ETX is a much more potent toxin and is responsible for enterotoxemia in animals, mainly sheep. ETX induces perivascular edema in various tissues and accumulates in particular in the kidneys and brain, where it causes edema and necrotic lesions. ETX is able to pass through the blood–brain barrier and stimulate the release of glutamate, which accounts for the symptoms of nervous excitation observed in animal enterotoxemia. At the cellular level, ETX causes rapid swelling followed by cell death involving necrosis. The precise mode of action of ETX remains to be determined. ETX is a powerful toxin, however, it also represents a unique tool with which to vehicle drugs into the central nervous system or target glutamatergic neurons.

Toxin Plasmids of Clostridium perfringens

“…Effects observed in naturally or experimentally intoxicated animals include edema in multiple organs, which probably reflects the effects of ETX on endothelial cells (3). Intriguingly, most endothelial cell lines are not sensitive to ETX, perhaps because they have lost receptor expression during culture (95).…”

“…Epsilon-toxin (ETX) ranks as the most potent clostridial toxin after botulinum and tetanus toxins (95,96). The toxin is secreted as a 296-amino-acid prototoxin, which is then proteolytically activated by digestive proteases such as chymotrypsin and trypsin or in vitro by C. perfringens lambda-toxin (97,98).…”

Comparative Neuropathology of Ovine Enterotoxemia Produced by Clostridium perfringens Type D Wild-Type Strain CN1020 and Its Genetically Modified Derivatives

“…3,23 While a direct and damaging effect of ETX on cerebral vascular endothelium is considered the fundamental basis of clinicopathologic changes in ETX-exposed sheep, the precise mechanism of this perturbation of the blood-brain barrier is incompletely understood. 19 We therefore used brains from lambs challenged with a wild-type strain of C. perfringens type D, its isogenic ETX null mutant, and an ETX-complemented strain, collected during a previous study, to investigate the pathogenesis of C. perfringens type D-mediated neurologic disease. 7 …”

Brain Lesions Associated WithClostridium perfringensType D Epsilon Toxin in a Holstein Heifer Calf

“…6 This is followed by a direct effect of ETX on brain endothelial cells causing cell damage and necrosis, increased vascular permeability, and cerebral edema as well as binding to myelin, astrocytes, and microglia. 6 The clinical signs of ETX intoxication could be a result of reduced vascular perfusion and hypoxia of the brain parenchyma surrounding affected blood vessels or a direct effect on the neuropil.…”