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Title: Role of the Vaccinia Virus E3 protein and its poxvirus orthologues in suppressing innate immune responses activated by RNA-based pathogen-associated molecular patterns
Authors: Myskiw, Chad
Supervisor: Cao, Jingxin (Medical Microbiology)
Examining Committee: Coombs, Kevin (Medical Microbiology) Gibson, Spencer (Biochemistry and Medical Genetics) Lin, Rongtuan (McGill University)
Graduation Date: February 2012
Keywords: poxvirus
Issue Date: Jul-2009
Publisher: American Society for Microbiology
Citation: Myskiw et al. J. Virol. 2009
Myskiw et al. J. Virology. 2011
Abstract: Poxviruses are a diverse family of double-stranded DNA viruses. A characteristic feature of poxviruses is that they express a vast array of immuno-modulatory proteins. Vaccinia virus is the prototypic member of the Orthopoxvirus genus, which also includes variola virus, the causative agent of smallpox. The vaccinia E3 protein is required for virus replication in vivo and in numerous cell culture systems. Although E3 function has received considerable study, many aspects of E3 biology remain to be addressed. While E3 can inhibit cytokine expression, the pathways targeted by E3 to block cytokine expression have not been identified. Furthermore, the factor(s) which stimulate innate immune responses during vaccinia infection are not known. In this study, E3 was found to target PKR and RIG-I-like receptor mediated signal transduction to differentially block expression of IFN-β, TNF-α and IL-6 in HeLa cells. RNA species generated in vaccinia infected cells were identified as pathogen-associated molecular patterns capable of inducing cytokine expression and activating apoptosis. Furthermore, PKR, RIG-I and MDA5 play non-overlapping and essential roles in mediating the innate immune response to these RNA species. Orthologues of E3 are encoded by all poxviruses which infect vertebrate animals except the Avipoxviruses and molluscum contagiosum virus. However, orthologues of vaccinia E3 remain essentially uncharacterized. A comparative analysis of the ability of E3 orthologues encoded by sheeppox, yaba monkey tumour, swinepox and myxoma virus to complement deletion of E3 was performed. E3 orthologues of myxoma virus and swinepox virus suppress PKR activation and interferon induced antiviral activity and restore the host range function of E3 in culture. In contrast, the E3 orthologues of sheeppox virus and yaba monkey tumour virus are unable to inhibit PKR activation. While the sheeppox orthologue cannot restore the host range function of E3, the yaba monkey tumour virus orthologue partially restores E3 deficient vaccinia replication. However, none of these E3 orthologues restore pathogenicity to E3 deficient vaccinia in vivo. In summary, these results highlight the role of the vaccinia virus E3 protein and its poxvirus orthologues in suppressing innate immune responses activated by RNA-based pathogen-associated molecular patterns
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