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Title: Degradation of Nuclear Factor Kappa B During Foot-and-Mouth Disease Virus Infection

Author
item De Los Santos, Teresa
item DIAZ-SAN SEGUNDO, FAYNA - USDA ORISE FELLOW
item Grubman, Marvin

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2007
Publication Date: 12/1/2007
Citation: De Los Santos, T., Diaz-San Segundo, F., Grubman, M.J. 2007. Degradation of Nuclear Factor Kappa B During Foot-and-Mouth Disease Virus Infection. Journal of Virology. 81(23):12803-12815.

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 (leaderless virus) that lacks a portion of the viral genome (lacks the leader protein). 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. Over the past few years we have initiated a program to understand the mechanism by which leaderless virus is attenuated. In the current study we demonstrate that the FMDV leader protein is involved in degrading a cellular protein that participates in inducing the host cell antiviral response. Thus, the presence of this protein in FMDV allows the virus to overcome the protective host response and replicate to high levels. 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 spread.

Technical Abstract: We have previously shown that the leader proteinase (L pro) of foot-and-mouth disease virus (FMDV) interferes with the innate immune response by blocking the translation of interferon (IFN) protein and by reducing the immediate-early induction of IFN-Beta mRNA and IFN stimulated genes. Here we report that L pro regulates the activity of nuclear factor Kappa B (NF-Kappa B). Analysis of NF-Kappa B dependent reporter gene expression in BHK-21 cells demonstrated that infection with wild-type (WT) virus has an inhibitory effect when compared to infection with a genetically engineered mutant lacking the leader coding region. Expression of endogenous NF-Kappa B dependent genes TNF' and RANTES is also reduced in WT virus infected primary porcine cells. This inhibitory effect is neither the result of a decrease in the level of the mRNA of p65/RelA, a subunit of NF-Kappa B, nor a block on nuclear translocation of p65/RelA, but instead appears to be a consequence of degradation of accumulated p65/RelA. Viral L pro is localized to the nucleus of infected cells and there is a correlation between the translocation of L pro and the decrease in the amount of nuclear p65/RelA. By using a recombinant cardiovirus expressing L pro we demonstrate that disappearance of p65/RelA takes place in the absence of any other FMDV product. The observation that L pro disrupts the integrity of NF-Kappa B suggests a global mechanism by which FMDV antagonizes the cellular innate immune and inflammatory responses to viral infection.