Date

12-2015

Document Type

Dissertation

Degree Name

Ph.D.

Department

Department of Molecular Microbiology and Immunology

Institution

Oregon Health & Science University

Abstract

Varicella Zoster Virus (VZV) causes chickenpox upon primary infection and establishes latency in ganglia. Reactivation from latency causes herpes zoster, which may be complicated by post-herpetic neuralgia. Innate immunity mediated by interferon and pro-inflammatory cytokines represents the first line of immune defense upon infection and reactivation. VZV is known to interfere with multiple innate immune signaling pathways including the central transcription factor NFĸB. However the role of these inhibitory mechanisms in vivo is unknown. Simian varicella virus (SVV)-infection of rhesus macaques recapitulates key aspects of VZV pathogenesis and this model thus permits examining the role of immune evasion mechanisms in vivo. Here we compare SVV and VZV with respect to interference of NFĸB activation. We demonstrate that both viruses prevent ubiquitination of the NFĸB inhibitor IĸBα, whereas SVV additionally prevents IĸBα phosphorylation. We show that the ORF61 proteins of VZV and SVV are sufficient to prevent IĸBα ubiquitination upon ectopic expression. We further demonstrate that SVV ORF61 interacts with β-TrCP, a subunit of the SCF ubiquitin ligase complex that mediates the degradation of IĸBα. This interaction seems to inactivate SCF-mediated protein degradation in general since the unrelated β-TrCP-target Snail is also stabilized by ORF61. In addition to ORF61, SVV seems to encode additional inhibitors of the NFĸB pathway since ORF61-deleted SVV still prevented IĸBα phosphorylation and degradation. Taken together, our data demonstrate that SVV interferes with TNFα-induced NFĸB activation at multiple levels which is consistent with the importance of these counter mechanisms for Varicella Virus infection.

Identifier

doi:10.6083/M4K07374

School

School of Medicine

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