|Diaz-San Segundo, Fayna -|
|De Los Santos, Teresa|
|Dias, Camila -|
Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 3, 2009
Publication Date: February 1, 2010
Citation: Diaz-San Segundo, F., Moraes, M.P., De Los Santos, T.B., Dias, C., Grubman, M.J. 2010. Interferon induced protection against foot-and-mouth disease virus correlates with enhanced tissue specific innate immune cell infiltration and interferon stimulated gene expression. Journal of Virology. 84:2063-2077. Interpretive Summary: Foot-and-mouth disease virus (FMDV) causes an economically devastating disease of cloven-hoofed animals including swine and cattle. Vaccines produced by chemical inactivation of virus as well as adenovirus vectored (Ad5) empty capsid vaccines are available, but neither induces protection prior to about 7 days postvaccination. In the event of an FMD outbreak in a disease-free country such as the U.S., it is necessary to induce immediate protection since FMDV replicates and spreads very rapidly. We have shown that in cell culture FMDV is inhibited by type I interferon (IFN), and we have developed recombinant Ad5s containing the genes for IFN alpha and beta. Swine administered one dose of Ad5 containing porcine IFN alpha and then challenged with virulent FMDV one day postinoculation were completely protected from clinical signs of disease and challenge virus replication. Likewise a combination of type I and type II IFNs protected swine from FMDV challenge. However, when we attempted to extend these studies to cattle, the animals were only partially protected from disease. Since this approach has not been completely effective we have attempted to develop a more comprehensive understanding of the mechanism(s) of IFN-induced protection against FMDV infection. Animals were inoculated with Ad5 viruses containing either IFN alpha or interferon gamma or the combination and the animals were challenged with FMDV one day later. Two animals from each group, and a control group, were euthanized at 1 day after Ad5-IFN administration, or 1 and 6 days after FMDV challenge. The animals were examined physically and serologically for clinical disease. In addition, we examined the skin and lymph nodes for possible immune cell recruitment and activation and blood and various tissues for induction of IFN stimulated genes. Our analysis suggests that IFN induced antiviral genes as well as IFN stimulated immune cell responses are both involved in protection against FMDV.
Technical Abstract: In previous studies we have demonstrated that type I interferon (IFN-alpha/beta) or a combination of IFN-alpha/beta and type II IFNs (IFN-gamma) delivered by replication-defective human adenovirus (Ad5) vectors can protect swine when challenged 1 day later with foot-and-mouth disease virus (FMDV). Protection correlated with the up-regulation of IFN stimulated genes (ISGs) in peripheral blood mononuclear cells. To gain a more comprehensive understanding of the mechanism of protection induced by IFNs, we inoculated groups of 6 swine with Ad5-vectors containing these genes, challenged 1 day later with FMDV and euthanized 2 animals from each group prior to (1 day postinoculation[dpi]) and at 1 (2 dpi) and 6 days postchallenge (dpc) (7 dpi). Blood, skin, and tissues from various immune system organs were taken at different times and examined for ISG induction and skin and lymph node infiltration by immune cells. All the animals in the IFN inoculated groups had delayed and decreased clinical signs of disease and viremia as compared to the controls and one animal in the IFN-alpha treated group did not develop clinical disease by 6 dpc. Prior to challenge and at 1 dpc (2 dpi) the groups inoculated with the IFNs had increased levels of dendritic cells and natural killer cells in the skin and lymph nodes, respectively, as compared to control animals as well as increased levels of several ISGs. All tissues examined from IFN-treated groups had significant up-regulation of the chemokine 10-kDa IFN-gamma-inducible protein.