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.
authors: California Animal Health and Food Safety Laboratory System-San Bernardino Branch, School of Veterinary Medicine, University of California, Davis, San Bernardino, CA, USA These authors contributed equally to the research and are joint first authors.
authors: J P
authors: JP
authors: Garcia
authors: California Animal Health and Food Safety Laboratory System-Davis Branch, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA These authors contributed equally to the research and are joint first authors.
authors: F
authors: F
authors: Giannitti
authors: SA Pathology, Hanson Institute Centre for Neurological Diseases and School of Veterinary Science, University of Adelaide, Adelaide, SA, Australia.
authors: J W
authors: JW
authors: Finnie
authors: SA Pathology, Hanson Institute Centre for Neurological Diseases and School of Veterinary Science, University of Adelaide, Adelaide, SA, Australia.
authors: J
authors: J
authors: Manavis
authors: California Animal Health and Food Safety Laboratory System-San Bernardino Branch, School of Veterinary Medicine, University of California, Davis, San Bernardino, CA, USA.
authors: J
authors: J
authors: Beingesser
authors: Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Department of Microbiology, Monash University, Victoria 3800, Australia.
authors: V
authors: V
authors: Adams
authors: Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Department of Microbiology, Monash University, Victoria 3800, Australia.
authors: J I
authors: JI
authors: Rood
authors: California Animal Health and Food Safety Laboratory System-San Bernardino Branch, School of Veterinary Medicine, University of California, Davis, San Bernardino, CA, USA fuzal@cahfs.ucdavis.edu.
authors: F A
authors: FA
authors: Uzal
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000032:analysis; D001921:Brain / Q000098:blood supply / Q000473:pathology*; D001923:Brain Chemistry; D003016:Clostridium perfringens / Q000235:genetics / Q000472:pathogenicity*; D004767:Enterotoxemia / Q000382:microbiology / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D012756:Sheep; D012757:Sheep Diseases / Q000382:microbiology / Q000473:pathology*
chemical_list: D051401:Aquaporin 4; D005904:Glial Fibrillary Acidic Protein
keywords: Clostridium perfringens type D; aquaporin; axonal injury; brain; edema; enterotoxemia; epsilon toxin; mutants