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Title: THE LEADER PROTEINASE OF FOOT-AND-MOUTH DISEASE VIRUS INHIBITS THE INDUCTION OF INTERFERON BETA MRNA AND BLOCKS THE HOST INNATE IMMUNE RESPONSE

Author
item De Los Santos, Teresa
item BOTTON, SONIA - FED UNIV OF SANTA MARIA B
item WEIBLEN, RUDI - FED UNIV OF SANTA MARIA B
item Grubman, Marvin

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2005
Publication Date: 2/1/2006
Citation: De Los Santos, T., Botton, S.D., Weiblen, R., Grubman, M.J. 2005. The Leader Proteinase of Foot-and-Mouth Disease Virus Inhibits the Induction of Interferon Beta mRNA and Blocks the Host Innate Immune Response. Journal of Virology.(2006) 80.4.1906-1914

Interpretive Summary: Foot-and-mouth disease virus (FMDV) causes an economically devastating disease of cloven-hoofed animals. To develop strategies necessary to control this disease it is important to understand how the virus and host interact. Identification of mechanisms that the host can utilize to rapidly control and contain virus replication may result in disease control approaches that are able to augment current and potential vaccine strategies. We have developed a weakened version of FMDV that lacks a portion of the viral genome (leaderless virus). This virus is highly attenuated when inoculated into cattle or swine, but can replicate to a limited extent. However, after aerosol infection of cattle the leaderless virus remained localized in the lungs and in contrast to virulent virus did not spread to other areas of the animal and cause disease. In certain cell cultures, we found that leaderless virus infection induced a host antiviral response that blocked virus spread and we have identified host proteins that directly inhibit virus replication. In the current study we demonstrate that the FMDV leader protein can block the host cell antiviral response at a number of levels thus allowing unrestricted virus replication. Understanding the mechanism of FMDV inhibition of the host antiviral response at the molecular level should be helpful in the development of specific antiviral strategies that can rapidly inhibit or limit virus spead.

Technical Abstract: We have previously shown that the leader proteinase (Lpro) of foot-and-mouth disease virus (FMDV) blocks cap-dependent mRNA translation and a genetically engineered FMDV lacking the leader proteinase coding region (A12-LLV2) is attenuated in cell culture and susceptible animals. The attenuated phenotype apparently is a consequence of the inability of A12-LLV2 to block the expression of type I interferon (IFN alpha/beta) protein resulting in IFN-induced inhibition of FMDV replication. Here we show that in addition to preventing IFN alpha/beta protein synthesis Lpro reduces the level of immediate-early induction of IFN beta mRNA and IFN stimulated genes such as dsRNA dependent protein kinase R (PKR), 2,5' oligoadenylate synthetase and Mx1 mRNAs in swine cells. Down-regulation of cellular PKR by RNA interference did not affect wild-type virus yield but resulted in a higher yield of A12-LLV2 indicating a direct role of PKR in controlling FMDV replication in the natural host. The observation that Lpro controls the transcription of genes involved in innate immunity reveals a novel role of this protein in antagonizing the cellular response to viral infection.