Understanding the infection processes of Bluetongue virus as a model of complex, non-enveloped orbiviruses: viruses with segmented double-stranded RNA genomes and multilayered capsids.
Bluetongue virus slips past a sheep’s cell defences by breaching the cell membrane and delivering a large, multi-layered capsid into the cytoplasm. This livestock pathogen causes periodic, severe outbreaks across Europe, yet key steps in its infection cycle have remained unclear because researchers lacked the tools to study them. New technologies now make it possible to ask how the virus enters cells, how it controls the release of its genetic material, and how newly assembled viral particles exit the cell. This project focuses on Bluetongue virus as a model for a whole family of related orbiviruses that share its complex structure and segmented double-stranded RNA genome. The work is fundamental science: it aims to reveal the molecular machinery of infection rather than produce an immediate vaccine or treatment. However, understanding these core processes could eventually inform strategies to block orbivirus outbreaks in livestock, reducing economic losses and improving animal health. Similar fundamental studies of viral entry and assembly have previously guided the development of antiviral drugs and vaccines for other pathogens.
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The overarching question addressed in this application is how do complex, non-enveloped orbiviruses (family Reoviridae) successfully invade host cells, replicate and cause disease. A related question is how this information can be used to better control virus outbreaks. Orbiviruses are arthropod-borne complex, multi-layered capsid viruses with segmented, double-stranded RNA genomes. Bluetongue Virus (BTV), the prototype of the orbivirus genus is a pathogen of livestock and is common throughout t he world including Europe, causing serious periodic outbreaks. Consequently it has been studied extensively as a model system for related viruses and substantial progress has been achieved in sequence, biochemical and structural studies of BTV. The studies of certain aspects of virus replication have been impeded however, for lack of appropriate tools and assay systems. However, recent advancement in technologies and assay systems now make it possible to obtain new information in these critical areas. This proposal addresses the most challenging key stages of the orbivirus life cycle and while focusing predominantly on BTV will apply to related viruses across the family. The key goals are to understand how BTV breaches the plasma membrane of the host cell to deliver a large capsid into the cytoplasm, how it regulates the release newly synthesized transcripts from the capsid into the cytoplasm and how transcription complexes become precisely located at the capsid vertices? Lastly, how do newly assembled subviral particles exit from their assembly site (factory) to leave the cell and the host factors and pathways involved in orbivirus infection in their diverse hosts?
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