title: Development and application of new mouse models to study the pathogenesis of Clostridium perfringens type C Enterotoxemias.
abstract: Clostridium perfringens type C isolates cause enterotoxemias and enteritis in humans and livestock. While the major disease signs and lesions of type C disease are usually attributed to beta toxin (CPB), these bacteria typically produce several different lethal toxins. Since understanding of disease pathogenesis and development of improved vaccines is hindered by the lack of small animal models mimicking the lethality caused by type C isolates, in this study we developed two mouse models of C. perfringens type C-induced lethality. When inoculated into BALB/c mice by intragastric gavage, 7 of 14 type C isolates were lethal, whereas when inoculated intraduodenally, these strains were all lethal in these mice. Clinical signs in intragastrically and intraduodenally challenged mice were similar and included respiratory distress, abdominal distension, and neurological alterations. At necropsy, the small, and occasionally the large, intestine was dilated and gas filled in most mice developing a clinical response. Histological changes in the gut were relatively mild, consisting of attenuation of the mucosa with villus blunting. Inactivation of the CPB-encoding gene rendered the highly virulent type C strain CN3685 avirulent in the intragastric model and nearly nonlethal in the intraduodenal model. In contrast, inactivation of the genes encoding alpha toxin and perfringolysin O only slightly decreased the lethality of CN3685. Mice could be protected against lethality by intravenous passive immunization with a CPB antibody prior to intragastric challenge. This study proves that CPB is a major contributor to the systemic effects of type C infections and provides new mouse models for investigating the pathogenesis of type C-induced lethality.
authors.affiliation: California Animal Health and Food Safety Laboratory System, San Bernardino Branch, School of Veterinary Medicine, University of California, Davis, San Bernardino, California 92408, USA. fuzal@cahfs.ucdavis.edu
authors.forename: Francisco A
authors.initials: FA
authors.lastname: Uzal
authors.forename: Juliann
authors.initials: J
authors.lastname: Saputo
authors.forename: Sameera
authors.initials: S
authors.lastname: Sayeed
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Vidal
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Fisher
authors.forename: Rachael
authors.initials: R
authors.lastname: Poon
authors.forename: Vicki
authors.initials: V
authors.lastname: Adams
authors.forename: Mariano E
authors.initials: ME
authors.lastname: Fernandez-Miyakawa
authors.forename: Julian I
authors.initials: JI
authors.lastname: Rood
authors.forename: Bruce A
authors.initials: BA
authors.lastname: McClane
mesh_terms: D000818:Animals; D000992:Antitoxins / Q000627:therapeutic use; D001427:Bacterial Toxins / Q000235:genetics / Q000633:toxicity; D002135:Calcium-Binding Proteins / Q000235:genetics; D003016:Clostridium perfringens / Q000472:pathogenicity*; D004195:Disease Models, Animal; D004386:Duodenum / Q000382:microbiology; D004767:Enterotoxemia / Q000473:pathology* / Q000503:physiopathology*; D017353:Gene Deletion; D006460:Hemolysin Proteins / Q000235:genetics; D007116:Immunization, Passive / Q000379:methods; D007413:Intestinal Mucosa / Q000473:pathology; D007420:Intestine, Large / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D013270:Stomach / Q000382:microbiology; D016019:Survival Analysis; D010738:Type C Phospholipases / Q000235:genetics
chemical_list: D000992:Antitoxins; D001427:Bacterial Toxins; C031884:CPB protein, Clostridium perfringens; D002135:Calcium-Binding Proteins; D006460:Hemolysin Proteins; C020452:Clostridium perfringens theta-toxin; D010738:Type C Phospholipases; C040649:alpha toxin, Clostridium perfringens