A Ferret Model of Canine Distemper Virus Virulence and Immunosuppression

Abstract

Canine distemper virus (CDV) infects many carnivores, including ferrets and dogs, and is the member of theMorbillivirus 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.

Tropism illuminated: Lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system

“…22. The B cell-derived cell line B95a (25) was used as host, thus limiting replication in nonlymphoid cells that may affect virulence.…”

“…CDV uses the same primary receptor (SLAM) as the other morbilliviruses (21), and, in small carnivores, it occupies the same ecological niche as MV in primates or rinderpest in ungulates. In ferrets, CDV infection causes a measles-like syndrome: disease signs include fever, whole body rash, drops in leukocyte numbers and lymphocyte proliferation activity, and respiratory and gastrointestinal symptoms (22). In ferrets, CDV is very virulent and causes animal death within 2-3 weeks, similar to infection of Bovidae with rinderpest (23).…”

Lymphotropism and host responses during acute wild-type canine distemper virus infections in a highly susceptible natural host

“…Members of the genus Morbillivirus within the family Paramyxoviridae include Measles virus (MV) of primates, Canine distemper virus (CDV) of carnivores and Rinderpest virus (RPV) of cloven-hoofed animals. Natural infections by all of these share common features, including lymphopenia and inhibition of lymphocyte proliferation in the acute phase (Griffin, 2007;Heaney et al, 2002;von Messling et al, 2003;Yanagi et al, 2006). Although live vaccines have effectively reduced the incidence of disease, the highly contagious morbilliviruses are still a major problem in human and veterinary medicine (Greene & Appel, 2006;Rima & Duprex, 2006).…”

“…The natural virus-host model in mink was selected because this and other mustelid species appear to be highly susceptible to wildtype CDV infections (Crook et al, 1958;Pearson & Gorham, 1987;von Messling et al, 2003).…”

N-(3-Cyanophenyl)-2-phenylacetamide, an effective inhibitor of morbillivirus-induced membrane fusion with low cytotoxicity

“…CNS complications are acute post-infectious measles encephalitis and, based on a persistent infection, subacute sclerosing pan-encephalitis (SSPE), which is always lethal. SSPE does not occur after measles vaccination (Duclos & Ward, 1998).CDV causes systemic infections similar to but distinct from human measles in carnivores such as canines, felids, ferrets, raccoons and seals, with lethality rates, depending on the host, of up to 100 % (Appel et al, 1972;Harder & Osterhaus, 1997;von Messling et al, 2003). In a high percentage of animals the CNS is infected, causing severe complications with infiltration of inflammatory cells and demyelination (Summers & Appel, 1994;.…”