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Title: Vaccinia virus protein C6 modulates innate immunity and contributes to virulence
Author: Sumner, Rebecca Pamela
ISNI:       0000 0004 2715 3701
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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To establish a productive infection pathogens must counteract the innate immune response. VACV is a large DNA virus that was used as the vaccine to eradicate smallpox and expresses many proteins that modulate the host response to the benefit of the virus. Protein C6, encoded by ORF 022 of VACV strain WR, is one such example. C6 is a small intracellular protein that is expressed early during infection and localises to both the nucleus and cytoplasm, and can form homo-dimers. This protein is a predicted member of the VACV Bcl-2 protein family and like other members of this family C6 possesses immunomodulatory properties. C6 is an inhibitor of IFNβ production, targeting the IRF3, but not the NF-κB, innate signalling pathway. C6 exerts its inhibitory effect at the level of the non-canonical IKK complex and TANK, SINTBAD and NAP1, important adaptor molecules for IFNβ activation, were identified as C6 interaction partners. C6 interacts with TANK via the N-terminal coiled-coil region of this adaptor, a domain that is shared amongst all three adaptor molecules. In addition C6 is an inhibitor of ISRE activation downstream of IFNα. Tandem affinity purification followed by mass spectrometry was used as a non-biased method to find interaction partners and identified UBR1, UBR2, Hsp70, SMARCC1, TROVE2 and VACV protein I1 as C6 binding partners. Of these, the interaction of C6 with UBR1 and SMARCC1 was confirmed by co-immunoprecipitation assays. Deletion of C6 from VACV strain WR had no effect on replication and spread in vitro, but significantly attenuated the virus in both the intranasal and intradermal models of murine infection. In addition, a virus lacking C6 had enhanced immunogenicity in a VACV challenge model, identifying this gene as a target for removal to improve VACV as a vaccine vector.
Supervisor: Mansur, Daniel ; Smith, Geoffrey Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral