Interferon-Induced Protection against Foot-and-Mouth Disease Virus Infection Correlates with Enhanced Tissue-Specific Innate Immune

Previously, we demonstrated that type I interferon (IFN-/) or a combination of IFN-/ and type II IFN (IFN-) delivered by a replication-defective human adenovirus 5 (Ad5) vector protected swine when challenged 1 day later with foot-and-mouth disease virus (FMDV). To gain a more comprehensive understanding of the mechanism of protection induced by IFNs, we inoculated groups of six swine with Ad5-vectors containing these genes, challenged 1 day later and euthanized 2 animals from each group prior to (1 day postinoculation [dpi]) and at 1 (2 dpi) and 6 days postchallenge (7 dpi). Blood, skin, and lymphoid tissues were examined for IFN-stimulated gene (ISG) induction and infiltration by innate immune cells. All IFN-inoculated animals had delayed and decreased clinical signs and viremia compared to the controls, and one animal in the IFN- treated group did not develop disease. At 1 and 2 dpi the groups inoculated with the IFNs had increased numbers of dendritic cells and natural killer cells in the skin and lymph nodes, respectively, as well as increased levels of several ISGs compared to the controls. In particular, all tissues examined from IFN-treated groups had significant upregulation of the chemokine 10-kDa IFN--inducible protein 10, and preferential upregulation of 2,5-oligoadenylate synthetase, Mx1, and indoleamine 2,3-dioxygenase. There was also up-regulation of monocyte chemotactic protein 1 and macrophage inflammatory protein 3 in the skin. These data suggest that there is a complex interplay between IFN-induced immunomodulatory and antiviral activities i