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Journal of Virology, December 2003, p. 12579-12591, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12579-12591.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Ferret Model of Canine Distemper Virus Virulence and Immunosuppression

Veronika von Messling, Christoph Springfeld, Patricia Devaux, and Roberto Cattaneo*

Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905

Received 15 May 2003/ Accepted 22 August 2003

Canine distemper virus (CDV) infects many carnivores, including ferrets and dogs, and is the member of the Morbillivirus genus most easily amenable to experimentation in a homologous small-animal system. To gain insights into the determinants of CDV pathogenesis, we isolated a strain highly virulent for ferrets by repeated passaging in these animals. Sequence comparison of the genome of this strain with that of its highly attenuated precursor revealed 19 mutations distributed almost evenly in the six genes. We then recovered a virus from a cDNA copy of the virulent CDV strain's consensus sequence by using a modified reverse genetics system based on B cells. We infected ferrets with this virus and showed that it fully retained virulence as measured by the timing of rash appearance, disease onset, and death. Body temperature, leukocyte number, lymphocyte proliferation activity, and cell-associated viremia also had similar kinetics. We then addressed the question of the relative importance of the envelope and other viral constituents for virulence. Viruses in which the envelope genes (matrix, fusion, and hemagglutinin) of the virulent strain were combined with the other genes of the attenuated strain caused severe rash and fever even if the disease onset was delayed. Viruses in which the nucleocapsid, polymerase, and phosphoprotein genes (coding also for the V and C proteins) of the virulent strain were combined with the envelope genes of the attenuated strain caused milder signs of disease. Thus, virulence-inducing mutations have accumulated throughout the genome.

* Corresponding author. Mailing address: Molecular Medicine Program, Mayo Foundation, Guggenheim 1838, 200 First St. SW, Rochester, MN 55905. Phone: (507) 284-0171. Fax: (507) 266-2122. E-mail: cattaneo.roberto{at}mayo.edu.

Journal of Virology, December 2003, p. 12579-12591, Vol. 77, No. 23
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.23.12579-12591.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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