New insights into Clostridium perfringens epsilon toxin activation and action on the brain during enterotoxemia.
Epsilon toxin (ETX), produced by Clostridium perfringens types B and D, is responsible for diseases that occur mostly in ruminants. ETX is produced in the form of an inactive prototoxin that becomes proteolytically-activated by several proteases. A recent ex vivo study using caprine intestinal contents demonstrated that ETX prototoxin is processed in a step-wise fashion into a stable, active ∼27 kDa band on SDS-PAGE. When characterized further by mass spectrometry, the stable ∼27 kDa band was shown to contain three ETX species with varying C-terminal residues; each of these ETX species is cytotoxic. This study also demonstrated that, in addition to trypsin and chymotrypsin, proteases such as carboxypeptidases are involved in processing ETX prototoxin. Once absorbed, activated ETX species travel to several internal organs, including the brain, where this toxin acts on the vasculature to cross the blood-brain barrier, produces perivascular edema and affects several types of brain cells including neurons, astrocytes, and oligodendrocytes. In addition to perivascular edema, affected animals show edema within the vascular walls. This edema separates the astrocytic end-feet from affected blood vessels, causing hypoxia of nervous system tissue. Astrocytes of rats and sheep affected by ETX show overexpression of aquaporin-4, a membrane channel protein that is believed to help remove water from affected perivascular spaces in an attempt to resolve the perivascular edema. Amyloid precursor protein, an early astrocyte damage indicator, is also observed in the brains of affected sheep. These results show that ETX activation in vivo seems to be more complex than previously thought and this toxin acts on the brain, affecting vascular permeability, but also damaging neurons and other cells.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
John C
JC
Freedman
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Bruce A
BA
McClane
California Animal Health and Food Safety Laboratory, San Bernardino Branch, School of Veterinary Medicine, University of California-Davis, San Bernardino, CA, USA. Electronic address: fuzal@cahfs.ucdavis.edu.
Francisco A
FA
Uzal
D000818:Animals; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism*; D001921:Brain / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D003016:Clostridium perfringens / Q000502:physiology*; D004767:Enterotoxemia / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D054884:Host-Pathogen Interactions; D006801:Humans; D007422:Intestines / Q000201:enzymology; D010447:Peptide Hydrolases / Q000502:physiology; D011498:Protein Precursors / Q000276:immunology / Q000378:metabolism*
D001427:Bacterial Toxins; C039811:Clostridium perfringens epsilon-toxin; D011498:Protein Precursors; D010447:Peptide Hydrolases
Clostridium perfringens; Enterotoxemia; Epsilon toxin; Intestinal proteases; Pore-forming toxin