1. Expression of porcine fusion protein IRF7/3(5D) efficiently controls foot-and-mouth disease virus replication.
- Author
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Ramírez-Carvajal L, Díaz-San Segundo F, Hickman D, Long CR, Zhu J, Rodríguez LL, and de los Santos T
- Subjects
- Adenoviridae genetics, Animals, Cattle, Cell Line, Foot-and-Mouth Disease immunology, Foot-and-Mouth Disease virology, Foot-and-Mouth Disease Virus genetics, Gene Expression immunology, Genetic Vectors, Humans, Interferon Inducers antagonists & inhibitors, Interferon Inducers immunology, Interferon Regulatory Factor-7 antagonists & inhibitors, Interferon Regulatory Factor-7 genetics, Interferon Type I antagonists & inhibitors, Interferon Type I biosynthesis, Interferon Type I immunology, Mice, Recombinant Fusion Proteins genetics, Swine, Vaccination, Vaccines, Synthetic, Viral Proteins pharmacology, Viral Vaccines administration & dosage, Virus Replication immunology, Adenoviridae immunology, Foot-and-Mouth Disease prevention & control, Foot-and-Mouth Disease Virus immunology, Interferon Regulatory Factor-7 immunology, Recombinant Fusion Proteins immunology, Viral Vaccines immunology
- Abstract
Unlabelled: Several studies have demonstrated that the delivery of type I, II, or III interferons (IFNs) by inoculation of a replication-defective human adenovirus 5 (Ad5) vector expressing IFNs can effectively control foot-and-mouth disease (FMD) in cattle and swine during experimental infections. However, relatively high doses are required to achieve protection. In this study, we identified the functional properties of a porcine fusion protein, poIRF7/3(5D), as a biotherapeutic and enhancer of IFN activity against FMD virus (FMDV). We showed that poIRF7/3(5D) is a potent inducer of type I IFNs, including alpha IFN (IFN-α), IFN-β, and IFN-ω but not type III IFN (interleukin-28B), without inducing cytotoxicity. Expression of poIRF7/3(5D) significantly and steadily reduced FMDV titers by up to 6 log10 units in swine and bovine cell lines. Treatment with an IFN receptor inhibitor (B18R) combined with an anti-IFN-α antibody neutralized the antiviral activity in the supernatants of cells transduced with an Ad5 vector expressing poIRF7/3(5D) [Ad5-poIRF7/3(5D)]. However, several transcripts with known antiviral function, including type I IFNs, were still highly upregulated (range of increase, 8-fold to over 500-fold) by poIRF7/3(5D) in the presence of B18R. Furthermore, the sera of mice treated with Ad5-poIRF7/3(5D) showed antiviral activity that was associated with the induction of high levels of IFN-α and resulted in complete protection against FMDV challenge at 6, 24, or 48 h posttreatment. This study highlights for the first time the antiviral potential of Ad5-poIRF7/3(5D) in vitro and in vivo against FMDV., Importance: FMD remains one of the most devastating diseases that affect livestock worldwide. Effective vaccine formulations are available but are serotype specific and require approximately 7 days before they are able to elicit protective immunity. We have shown that vector-delivered IFN is an option to protect animals against many FMDV serotypes as soon as 24 h and for about 4 days postadministration. Here we demonstrate that delivery of a constitutively active transcription factor that induces the production of endogenous IFNs and potentially other antiviral genes is a viable strategy to protect against FMD., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
- Published
- 2014
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