Role of the innate immune response in canine distemper virus neuropathogenesis

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Canine distemper virus (CDV) causes a severe systemic disease in a broad range of carnivores. In addition, up to 30% of dogs experience involvement of the central nervous system (CNS), making CDV well suited for the characterization of Morbillivirus-induced neuropathogenetic mechanisms. In the CNS, CDV causes acute and chronic demyelinating lesions, which are partially of immunopathogenic origin. Since the CDV V-protein plays an essential role in the inhibition of antiviral responses, I hypothesize that CDV-associated inflammatory CNS lesions and subsequent demyelination result from an insufficient infection control by the innate immune response during the acute disease phase.To test this hypothesis, I am proposing a research plan with two specific aims:(a) To assess the ability of CDV to inhibit the interferon (IFN) signaling cascade in different primary mustelid and canine cell types, and (b) to characterize the dissemination, target cells, and the local innate immune response of wild type and V-deleted viruses in mustelid organotypic brain slice cultures.For (a) I will determine the replication efficiency in different primary mustelid and canine CNS cell types, primary epithelial cells, and peripheral blood mononuclear cells. I will also measure the type I IFN production using a VSV-bioassay to investigate a correlation between replication efficiency with the extent of innate immune activation. For (b) I will first compare the spread and target cells of the two viruses by immunohistochemistry, and assess the innate immune activation by VSV-bioassay and cytokine expression levels using real-time RT-PCR and Western blot analysis. The cytokine-expressing cells will then be identified by double-staining of tissue sections.Summarized, the proposed work will advance our understanding of the host response contribution to morbillivirus-associated neurologic complications and will constitute the basis for the development of a targeted preventative therapy.