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Molecular pathogenesis of murid herpesvirus-4 latent infection

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Resumo:The major biological characteristic of herpesviruses is their ability to establish life-long latent infections in specific cell types within their host. In particular, gammaherpesviruses typically colonise their hosts by driving the proliferation of infected B cells in germinal centres (GCs) and establishing a lifelong reservoir of latently infected memory B cells. These events are controlled by viral proteins that subvert host cell signalling pathways by regulating or replacing functionally specific signalling proteins. These viral proteins are of particular interest as they constitute key components of gammaherpesvirus pathogenesis and a potential link to virus associatedoncogenic transformation. One of such proteins is the latency-associated M2 protein of murid herpesvirus-4 (MuHV-4). M2 has been shown to act as an adaptor molecule, mediating the assembly of multiprotein complexes that favour the interaction between enzymes and substrates, and thus mediate the modulation of B cell signalling pathways downstream of the B cell receptor (BCR). The central aim of this research was to determine at which stage of the MuHV-4 viral life cycle M2 is performing these biochemical functions and how important they are for normal host colonization. To this end, recombinant viruses with disruptive mutations in M2 domains, which are essential for binding and modulating the activity of B cell signalling proteins, were engineered. The ability of these recombinant viruses to establish and maintain a latent infection was analysed upon intranasal infection of mice. Infection of mice with recombinant viruses resulted in a delay in the seeding of splenic follicles and in the expansion of latency in GC B cells. The role of M2 in MuHV-4 infection of other cell types, namely dendritic cells and macrophages, was also assessed. No evidence was found supporting a function for M2 in these cells. Overall, these studies reveal that M2 functions in vivo as a modulator of B cell signalling pathways and that this crosstalk is critical in the process of viral latency, for the efficient colonization of splenic follicles.
Autores principais:Alenquer, Marta Bebiano
Assunto:Gammaherpesvirinae Latência viral Linfócitos B Herpesviridae Teses de doutoramento - 2010
Ano:2010
País:Portugal
Tipo de documento:tese de doutoramento
Tipo de acesso:acesso aberto
Instituição associada:Universidade de Lisboa
Idioma:inglês
Origem:Repositório da Universidade de Lisboa

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