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oai:www.ideals.illinois.edu:2142/18499 2023-07-10 col_2142_5131 col_2142_16338 com_2142_5130 com_2142_16337 com_2142_14793 com_2142_8903

http://hdl.handle.net/2142/18499 en Copyright 2010 Kristen Willis vaccinia virus protein kinase (PKR) NF-kappaB K1 protein Characterization of the anti-viral effects inhibited by the vaccinia virus K1 protein Vaccinia virus (VV), a member of the poxvirus family of double-stranded DNA viruses, is well-known as a highly effective vaccine against variola virus, the causative agent of smallpox. Poxviruses encode many strategies to evade the host immune and anti-viral response. One such host anti-viral response, activation of the double-stranded RNA activated protein kinase (PKR) pathway, is important in sensing the presence of intracellular viral genomes and their products. PKR is activated by dsRNA, a by-product of many virus infections, and exhibits its anti-viral effects in part via inhibition of protein synthesis and activation of the pro-inflammatory transcription factor NF-κB. I have identified the vaccinia virus K1 protein as an inhibitor of PKR activation. I determined that the C-terminal portion of the 2nd ankyrin repeat, a motif important for protein-protein interactions, is important for this inhibitory function. Further, K1 mediated PKR inhibition also blocks activation of downstream NF-κB in VV infected cells. Previous characterization of the K1 protein identified it as a host-range protein required for a productive infection. When the K1L gene is absent, replication is aborted due to shut-down in viral protein synthesis. I queried whether PKR was responsible for this effect. I found that replication when K1 was lacking could not be rescued by depletion of PKR protein levels. Hence K1 inhibition of PKR is not related to the host-range function. I next identified that the trigger for PKR activation is viral dsRNAs derived from early or intermediate viral transcription. As early dsRNAs have never been reported during a poxvirus infection, this finding was novel. Further, I found that there were higher levels of dsRNA present during a VV infection when K1 was absent or mutated. Finally, ectopic expression of K1 was able to inhibit PKR activation induced by viral dsRNAs. Together these data identifies a new function for the K1 protein and elucidates a strategy viruses utilize to inhibit detrimental host cell responses. Item withdrawn by Mark Zulauf (zulauf@illinois.edu) on 2010-09-28T17:55:57Z Item was in collections: University of Illinois Theses & Dissertations (ID: 1) No. of bitstreams: 1 Willis_Kristen.pdf: 2310797 bytes, checksum: fb82ffb8ab6e191c1537f32f0675a58c (MD5) Made available in DSpace on 2011-01-21T22:43:05Z (GMT). No. of bitstreams: 2 Willis_Kristen.pdf: 2310797 bytes, checksum: fb82ffb8ab6e191c1537f32f0675a58c (MD5) license.txt: 4062 bytes, checksum: 2aaa33f7eb9e99ec4f72979262432df2 (MD5) Item marked as restricted to the 'UIUC Users [automated]' Group (id=2) by William Ingram (wingram2@illinois.edu) on 2011-01-21T22:47:50Z Item is restricted until 2013-01-21T22:47:37Z Shisler, Joanna L. Shisler, Joanna L. Cronan, John E. Blanke, Steven R. Metcalf, William W. Willis, Kristen L. 2011-01-21T22:43:05Z 2011-01-21T22:43:05Z 2013-01-22T11:00:24Z 2011-01-21T22:43:05Z 2010-12 Item reinstated by Sarah Shreeves (sshreeve@illinois.edu) on 2013-01-22T11:00:24Z Item was in collections: University of Illinois Dissertations and Theses (ID: 204) Dissertations - Microbiology (ID: 748) No. of bitstreams: 2 Willis_Kristen.pdf: 2310797 bytes, checksum: fb82ffb8ab6e191c1537f32f0675a58c (MD5) license.txt: 4062 bytes, checksum: 2aaa33f7eb9e99ec4f72979262432df2 (MD5) Item released from any restrictions by Sarah Shreeves (sshreeve@illinois.edu) on 2013-01-22T11:00:24Z Microbiology 1948 Microbiology 0322 University of Illinois at Urbana-Champaign Dissertation Ph.D. PHD:Microbiology -UIUC 10KS0322PHD