We previously demonstrated that the ability of foot-and-mouth disease virus (FMDV) to form plaques in cell culture is associated with the suppression of alpha/beta interferon (IFN-␣/␤). In the present study, we used Escherichia coli-expressed porcine and bovine IFN-␣ or -␤ individually to demonstrate that each was equally effective in inhibiting FMDV replication. The block in FMDV replication appeared to be at the level of protein translation, suggesting a role for double-stranded RNA-dependent protein kinase (PKR). In support of these findings, treatment of porcine and bovine cells with 2-aminopurine, an inhibitor of PKR, increased the yield of virus 8.8-and 11.2-fold, respectively, compared to that in untreated infected cells. In addition, results of FMDV infection in mouse embryonic fibroblast cells derived from gene knockout mice lacking the gene for RNase L ؊/؊ or PKR ؊/؊ or both indicated an important role for PKR in the inhibition of FMDV replication.

We have previously shown that replication of foot-and-mouth disease virus (FMDV) is highly sensitive to alpha/beta interferon (IFN-␣/␤). In the present study, we constructed recombinant, replication-defective human adenovirus type 5 vectors containing either porcine IFN-␣ or IFN-␤ (Ad5-pIFN␣ or Ad5-pIFN␤). We demonstrated that cells infected with these viruses express high levels of biologically active IFN. Swine inoculated with 10 9 PFU of a control Ad5 virus lacking the IFN gene and challenged 24 h later with FMDV developed typical signs of foot-and-mouth disease (FMD), including fever, vesicular lesions, and viremia. In contrast, swine inoculated with 10 9 PFU of Ad5-pIFN␣ were completely protected when challenged 24 h later with FMDV. These animals showed no clinical signs of FMD and no viremia and did not develop antibodies against viral nonstructural proteins, suggesting that complete protection from infection was achieved.

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Previously, we showed that type I interferon (alpha/beta interferon [IFN-␣/␤]) can inhibit foot-and-mouth disease virus (FMDV) replication in cell culture, and swine inoculated with 10 9 PFU of human adenovirus type 5 expressing porcine IFN-␣ (Ad5-pIFN-␣) were protected when challenged 1 day later. In this study, we found that type II pIFN (pIFN-␥) also has antiviral activity against FMDV in cell culture and that, in combination with pIFN-␣, it has a synergistic antiviral effect. We also observed that while each IFN alone induced a number of IFN-stimulated genes (ISGs), the combination resulted in a synergistic induction of some ISGs. To extend these studies to susceptible animals, we inoculated groups of swine with a control Ad5,

Foot-and-mouth disease (FMD) is one of the most serious threats to the livestock industry. Despite the availability of a vaccine, recent outbreaks in disease-free countries have demonstrated that development of novel FMD control strategies is imperative. Here we report the identification and characterization of bovine (bo) interferon lambda 3 (IFN-λ3), a member of the type III IFN family. Expression of boIFN-λ3 using a replication-defective human adenovirus type 5 vector (Ad5-boIFN-λ3) yielded a glycosylated secreted protein with antiviral activity against FMD virus (FMDV) and vesicular stomatitis virus in bovine cell culture. Inoculation of cattle with Ad5-boIFN-λ3 induced systemic antiviral activity and up-regulation of IFN stimulated gene expression in multiple tissues susceptible to FMDV infection. Our results demonstrate that the type III IFN family is conserved in bovines and boIFN-λ3 has potential for further development as a biotherapeutic candidate to inhibit FMDV or other viruses in cattle.