Submitted to: American Society for Virology Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 6/2/2009
Publication Date: 7/10/2009
Citation: De Los Santos, T.B., Grubman, M.J., Zhu, J.J. 2009. Functional genomics approach to understand the role of Lpro in FMDV virulence. American Society for Virology Meeting. Paper No. 9-21: P.262. Interpretive Summary:
Technical Abstract: The leader proteinase (Lpro) of foot-and-mouth disease virus (FMDV) plays a critical role in viral pathogenesis. Viruses lacking the Lpro coding region (leaderless virus) are highly attenuated in cell culture and in the natural host, ie. swine and bovine. Molecular studies have demonstrated that Lpro inhibits host cap-dependent mRNA translation resulting in decreased expression of interferons (IFNs) which allows for rapid virus growth and spread. Recently we have demonstrated that Lpro is also involved in blocking mRNA transcription, particularly transcription controlled by nuclear factor-kappa B (NF-kappa B). To systematically study the molecular mechanisms involved in Lpro inhibition of transcription we have taken a functional genomics approach using micro-array technology. Primary embryonic bovine kidney cells were infected with wild-type (WT) or leaderless virus and the whole genome expression profile was analyzed at different times post infection. Out of approximately 42,000 gene probes, 39 genes were up-regulated in leaderless as compared to WT virus infected cells. Most of the up-regulated genes correspond to IFN-inducible genes, chemokines or transcription factors. Promoter sequence analysis suggested that the transcription factors NF-kappa B, ISGF-3 and IRF1 specifically contributed to the differential gene expression. Statistical analysis indicates that NF-kappa B is the primary effector of the differential expression. These results support the previously identified role of Lpro in inhibition of host cell transcription and provide evidence that its primary effect is interference with the NF-kappa B signaling pathway.