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Infection and Immunity, December 2009, p. 5291-5299, Vol. 77, No. 12
0019-9567/09/$08.00+0 doi:10.1128/IAI.00825-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Development and Application of New Mouse Models To Study the Pathogenesis of Clostridium perfringens Type C Enterotoxemias
Francisco A. Uzal,1*
Juliann Saputo,1
Sameera Sayeed,2,
Jorge E. Vidal,2,
Derek J. Fisher,2,3,
Rachael Poon,4
Vicki Adams,4
Mariano E. Fernandez-Miyakawa,1,¶
Julian I. Rood,4 and
Bruce A. McClane2,3,4
California Animal Health and Food Safety Laboratory System, San Bernardino Branch, School of Veterinary Medicine, University of California, Davis, San Bernardino, California 92408,1 Department of Microbiology and Molecular Genetics,2 Molecular Virology and Microbiology Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261,3 Australian Research Council Centre of Excellence in Structural and Functional Microbial Genomics, Department of Microbiology, Monash University, Victoria 3800, Australia4
Received 23 July 2009/ Returned for modification 16 August 2009/ Accepted 12 September 2009
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.
* Corresponding author. Mailing address: California Animal Health and Food Safety Laboratory-San Bernardino Branch, University of California-Davis, 105 West Central Avenue, San Bernardino, CA 92408. Phone: (909) 383-4287. Fax: (909) 884-5980. E-mail: fuzal{at}cahfs.ucdavis.edu
Published ahead of print on 5 October 2009.
Present address: Science Department, Marywood University, Scranton, PA 18509.
Present address: Rollins School of Public Health, Emory University, Atlanta, GA.
Present address: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD.
¶ Present address: Instituto de Patobiología, Instituto Nacional de Tecnología Agropecuaria, Castelar, Buenos Aires, Argentina.
Infection and Immunity, December 2009, p. 5291-5299, Vol. 77, No. 12
0019-9567/09/$08.00+0 doi:10.1128/IAI.00825-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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