Rudd, Penny Ann
Characterization of canine distemper virus neuroinvasion using a ferret model of infection
Québec, Université du Québec, Institut National de la Recherche Scientifique, Doctorat en virologie et immunologie, 217 p.
Morbilliviruses cause an acute disease characterized by rash, respiratory and gastrointestinal signs, and severe immunosuppression. In addition, neurological complications can occur and the prevalence varies within the genus. The highest incidence of CNS involvement is associated with canine distemper virus (CDV), with up to 30% of ali acute cases resulting in encephalopathies. Only one in a thousand people infected with measles virus experience neurological involvement, whereas neurological disease in ungulate morbilliviruses is exceedingly rare.
To characterize mechanisms of morbillivirus pathogenesis, our laboratory has developed a small animal model, using the ferret, to better understand morbillivirus pathogenesis and immunosuppression. Ferrets are natural hosts for CDV, and develop the typical rash, fever, severe leukopenia, gastrointestinal and respiratory signs of disease. Also, when inoculated with wild type strains, ferrets succumb to the infection with i n two to five weeks. The goal of my thesis was to characterize the events which lead up to and occur during the acute phase of CDV central nervous system (CNS) infection in ferrets. ln order to accomplish this, three specifie objectives were defined.
The first research objective was to determine the pathways involved in CDV neuroinvasion and to identify the cell types targeted by the virus. By using histology and confocal microscopy, we showed that CDV not only enters the CNS by the hematogenous route but, as previously suggested in studi es with dogs, also uses the olfactory pathway.
In the second objective we investigated the kinetics of CDV neurodissemination and the resulting damage that arises at early disease stages during acute encephalitis. Towards this, a recombinant virus of the hi ghly neurovirulent strain Snyder Hill was constructed and we observed that despite a generalized immunosuppression, infected animais developed a strong local inflammatory response. This response was characteri zed by the presence of activated microglia, gliosis in highly infected brain regions and the expression of the pro-inflammatory cytokines interleukin-6, interferon-() and tumor necrosis factor-a.
For the final objective, we wanted to investigate the transneuronal spread of morbilliviruses. An in vitro model of infection using a primary culture of ferret neurons was established and we demonstrated that this model mimics many key aspects of CDV infection seen in vivo. We observed that CDV spreads non-directionally along communicating neurons and determined that cell-cell contact is required for efficient transneuronal dissemination. Although its development is still very recent, this system will be useful to examine in more detail the mechanisms involved in morbillivirus transneuronalspread.
Taken together my work contributes to a better understanding of the events involved in morbillivirus CNS infection and may lead to new treatment strategies to limit CNS sequelae or even to prevent CNS invasion.
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