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

J. P. Garcia, F. Giannitti, J. W. Finnie, J. Manavis, J. Beingesser, V. Adams, J. I. Rood, Francisco A Uzal

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Clostridium perfringens type D causes enterotoxemia in sheep and goats. The disease is mediated by epsilon toxin (ETX), which affects the cerebrovascular endothelium, increasing vascular permeability and leading to cerebral edema. In the present study, we compared the distribution and severity of the cerebrovascular changes induced in lambs by C. perfringens type D strain CN1020, its isogenic etx null mutant, and the ETX-producing complemented mutant. We also applied histochemical and immunohistochemical markers to further characterize the brain lesions induced by ETX. Both ETX-producing strains induced extensive cerebrovascular damage that did not differ significantly between each other in nature, neuroanatomic distribution, or severity. By contrast, lambs inoculated with the etx mutant or sterile, nontoxic culture medium did not develop detectable brain lesions, confirming that the neuropathologic effects observed in these infections are dependent on ETX production. Lambs treated with the wild-type and complemented strains showed perivascular and mural vascular edema, as well as serum albumin extravasation, particularly severe in the cerebral white matter, midbrain, medulla oblongata, and cerebellum. Brains of animals inoculated with the ETX-producing strains showed decreased expression of glial fibrillary acidic protein and increased expression of aquaporin-4 in the end-feet processes of the astrocytes around blood vessels. Early axonal injury was demonstrated with anti–amyloid precursor protein immunohistochemistry. Perivascular accumulation of macrophages/microglia with intracytoplasmic albumin globules was also observed in these animals. This study demonstrates that ETX is responsible for the major cerebrovascular changes in C. perfringens type D–induced disease.

Original languageEnglish (US)
Pages (from-to)465-475
Number of pages11
JournalVeterinary Pathology
Volume52
Issue number3
DOIs
StatePublished - May 3 2015

Fingerprint

Enterotoxemia
Clostridium perfringens D
enterotoxemia
neuropathology
Clostridium perfringens
Sheep
toxins
chemical derivatives
sheep
Blood Vessels
Brain
Aquaporin 4
blood vessels
Medulla Oblongata
Protein Precursors
brain
Glial Fibrillary Acidic Protein
Brain Edema
Capillary Permeability
Microglia

Keywords

  • aquaporin
  • axonal injury
  • brain
  • Clostridium perfringens type D
  • edema
  • enterotoxemia
  • epsilon toxin
  • mutants

ASJC Scopus subject areas

  • veterinary(all)

Cite this

Comparative Neuropathology of Ovine Enterotoxemia Produced by Clostridium perfringens Type D Wild-Type Strain CN1020 and Its Genetically Modified Derivatives. / Garcia, J. P.; Giannitti, F.; Finnie, J. W.; Manavis, J.; Beingesser, J.; Adams, V.; Rood, J. I.; Uzal, Francisco A.

In: Veterinary Pathology, Vol. 52, No. 3, 03.05.2015, p. 465-475.

Research output: Contribution to journalArticle

Garcia, J. P. ; Giannitti, F. ; Finnie, J. W. ; Manavis, J. ; Beingesser, J. ; Adams, V. ; Rood, J. I. ; Uzal, Francisco A. / Comparative Neuropathology of Ovine Enterotoxemia Produced by Clostridium perfringens Type D Wild-Type Strain CN1020 and Its Genetically Modified Derivatives. In: Veterinary Pathology. 2015 ; Vol. 52, No. 3. pp. 465-475.
@article{930762610ca44573a685fdc9174ba9ed,
title = "Comparative Neuropathology of Ovine Enterotoxemia Produced by Clostridium perfringens Type D Wild-Type Strain CN1020 and Its Genetically Modified Derivatives",
abstract = "Clostridium perfringens type D causes enterotoxemia in sheep and goats. The disease is mediated by epsilon toxin (ETX), which affects the cerebrovascular endothelium, increasing vascular permeability and leading to cerebral edema. In the present study, we compared the distribution and severity of the cerebrovascular changes induced in lambs by C. perfringens type D strain CN1020, its isogenic etx null mutant, and the ETX-producing complemented mutant. We also applied histochemical and immunohistochemical markers to further characterize the brain lesions induced by ETX. Both ETX-producing strains induced extensive cerebrovascular damage that did not differ significantly between each other in nature, neuroanatomic distribution, or severity. By contrast, lambs inoculated with the etx mutant or sterile, nontoxic culture medium did not develop detectable brain lesions, confirming that the neuropathologic effects observed in these infections are dependent on ETX production. Lambs treated with the wild-type and complemented strains showed perivascular and mural vascular edema, as well as serum albumin extravasation, particularly severe in the cerebral white matter, midbrain, medulla oblongata, and cerebellum. Brains of animals inoculated with the ETX-producing strains showed decreased expression of glial fibrillary acidic protein and increased expression of aquaporin-4 in the end-feet processes of the astrocytes around blood vessels. Early axonal injury was demonstrated with anti–amyloid precursor protein immunohistochemistry. Perivascular accumulation of macrophages/microglia with intracytoplasmic albumin globules was also observed in these animals. This study demonstrates that ETX is responsible for the major cerebrovascular changes in C. perfringens type D–induced disease.",
keywords = "aquaporin, axonal injury, brain, Clostridium perfringens type D, edema, enterotoxemia, epsilon toxin, mutants",
author = "Garcia, {J. P.} and F. Giannitti and Finnie, {J. W.} and J. Manavis and J. Beingesser and V. Adams and Rood, {J. I.} and Uzal, {Francisco A}",
year = "2015",
month = "5",
day = "3",
doi = "10.1177/0300985814540543",
language = "English (US)",
volume = "52",
pages = "465--475",
journal = "Veterinary Pathology",
issn = "0300-9858",
publisher = "SAGE Publications Ltd",
number = "3",

}

TY - JOUR

T1 - Comparative Neuropathology of Ovine Enterotoxemia Produced by Clostridium perfringens Type D Wild-Type Strain CN1020 and Its Genetically Modified Derivatives

AU - Garcia, J. P.

AU - Giannitti, F.

AU - Finnie, J. W.

AU - Manavis, J.

AU - Beingesser, J.

AU - Adams, V.

AU - Rood, J. I.

AU - Uzal, Francisco A

PY - 2015/5/3

Y1 - 2015/5/3

N2 - Clostridium perfringens type D causes enterotoxemia in sheep and goats. The disease is mediated by epsilon toxin (ETX), which affects the cerebrovascular endothelium, increasing vascular permeability and leading to cerebral edema. In the present study, we compared the distribution and severity of the cerebrovascular changes induced in lambs by C. perfringens type D strain CN1020, its isogenic etx null mutant, and the ETX-producing complemented mutant. We also applied histochemical and immunohistochemical markers to further characterize the brain lesions induced by ETX. Both ETX-producing strains induced extensive cerebrovascular damage that did not differ significantly between each other in nature, neuroanatomic distribution, or severity. By contrast, lambs inoculated with the etx mutant or sterile, nontoxic culture medium did not develop detectable brain lesions, confirming that the neuropathologic effects observed in these infections are dependent on ETX production. Lambs treated with the wild-type and complemented strains showed perivascular and mural vascular edema, as well as serum albumin extravasation, particularly severe in the cerebral white matter, midbrain, medulla oblongata, and cerebellum. Brains of animals inoculated with the ETX-producing strains showed decreased expression of glial fibrillary acidic protein and increased expression of aquaporin-4 in the end-feet processes of the astrocytes around blood vessels. Early axonal injury was demonstrated with anti–amyloid precursor protein immunohistochemistry. Perivascular accumulation of macrophages/microglia with intracytoplasmic albumin globules was also observed in these animals. This study demonstrates that ETX is responsible for the major cerebrovascular changes in C. perfringens type D–induced disease.

AB - Clostridium perfringens type D causes enterotoxemia in sheep and goats. The disease is mediated by epsilon toxin (ETX), which affects the cerebrovascular endothelium, increasing vascular permeability and leading to cerebral edema. In the present study, we compared the distribution and severity of the cerebrovascular changes induced in lambs by C. perfringens type D strain CN1020, its isogenic etx null mutant, and the ETX-producing complemented mutant. We also applied histochemical and immunohistochemical markers to further characterize the brain lesions induced by ETX. Both ETX-producing strains induced extensive cerebrovascular damage that did not differ significantly between each other in nature, neuroanatomic distribution, or severity. By contrast, lambs inoculated with the etx mutant or sterile, nontoxic culture medium did not develop detectable brain lesions, confirming that the neuropathologic effects observed in these infections are dependent on ETX production. Lambs treated with the wild-type and complemented strains showed perivascular and mural vascular edema, as well as serum albumin extravasation, particularly severe in the cerebral white matter, midbrain, medulla oblongata, and cerebellum. Brains of animals inoculated with the ETX-producing strains showed decreased expression of glial fibrillary acidic protein and increased expression of aquaporin-4 in the end-feet processes of the astrocytes around blood vessels. Early axonal injury was demonstrated with anti–amyloid precursor protein immunohistochemistry. Perivascular accumulation of macrophages/microglia with intracytoplasmic albumin globules was also observed in these animals. This study demonstrates that ETX is responsible for the major cerebrovascular changes in C. perfringens type D–induced disease.

KW - aquaporin

KW - axonal injury

KW - brain

KW - Clostridium perfringens type D

KW - edema

KW - enterotoxemia

KW - epsilon toxin

KW - mutants

UR - http://www.scopus.com/inward/record.url?scp=84930146106&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930146106&partnerID=8YFLogxK

U2 - 10.1177/0300985814540543

DO - 10.1177/0300985814540543

M3 - Article

C2 - 24964921

AN - SCOPUS:84930146106

VL - 52

SP - 465

EP - 475

JO - Veterinary Pathology

JF - Veterinary Pathology

SN - 0300-9858

IS - 3

ER -