Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: April 11, 2006
Publication Date: July 15, 2006
Citation: De Los Santos, T., Brum, M., Grubman, M.J. 2006. The leader proteinase of foot-and-mouth disease virus reduces the expression of interferon by suppressing the activity of the nuclear factor kappa b. American Society of Virology Annual Meeting. 2006. P. 67. Technical Abstract: We have previously shown that the leader proteinase of foot-and-mouth disease virus (FMDV) is involved in antagonizing the innate immune response by inhibiting the translation of interferon (IFN) mRNA and the immediate-early induction of IFN'beta mRNA. These results correlated with the attenuated phenotype, in both cell culture and susceptible animals, of a genetically engineered FMDV variant lacking the leader proteinase coding region (leaderless virus). To determine the molecular mechanism(s) of suppression of IFN'beta'transcription we have examined the activity of transcription factors involved in this process. BHK-21 cells were transfected with plasmids containing a luciferase reporter gene under the control of promoter regions containing regulatory sequences for nuclear factor kappa B (NF'kappa B), interferon regulatory factor 3 (IRF3), and AP-1. Transfected cells were infected with wild-type (WT) FMDV or leaderless virus and cell lysates were analyzed for reporter activity at various times postinfection. Our results indicate that leader proteinase down-regulates the transcriptional activity of NF kappa B. Consistent with these results, infection of porcine cells with leaderless virus induced higher levels of mRNA for the NF'kappa'B inducible cytokine TNF alpha and the chemokine RANTES when compared to infection with WT virus. We are currently examining the effect of leader proteinase on the various steps involved in NF'kappa'B recruitment. Analysis of the activation of IRF3 including phosphorylation, dimerization, and translocation, suggested that FMDV does not have a direct inhibitory role on these processes. Similarly, preliminary studies indicate that FMDV does not affect AP-1 activation. Thus, FMDV, like many other viruses, has evolved multiple mechanisms to counteract the host innate immune response.