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.
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Authors | Lisbeth Ramírez-Carvajal, Fayna Díaz-San Segundo, Danielle Hickman, Charles R Long, James Zhu, Luis L Rodríguez, Teresa de los Santos |
Journal | Journal of virology
(J Virol)
Vol. 88
Issue 19
Pg. 11140-53
(Oct 2014)
ISSN: 1098-5514 [Electronic] United States |
PMID | 25031341
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014, American Society for Microbiology. All Rights Reserved. |
Chemical References |
- Interferon Inducers
- Interferon Regulatory Factor-7
- Interferon Type I
- Recombinant Fusion Proteins
- Vaccines, Synthetic
- Viral Proteins
- Viral Vaccines
- B18R protein, Vaccinia virus
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Topics |
- Adenoviridae
(genetics, immunology)
- Animals
- Cattle
- Cell Line
- Foot-and-Mouth Disease
(immunology, prevention & control, virology)
- Foot-and-Mouth Disease Virus
(genetics, immunology)
- Gene Expression
(immunology)
- Genetic Vectors
- Humans
- Interferon Inducers
(antagonists & inhibitors, immunology)
- Interferon Regulatory Factor-7
(antagonists & inhibitors, genetics, immunology)
- Interferon Type I
(antagonists & inhibitors, biosynthesis, immunology)
- Mice
- Recombinant Fusion Proteins
(genetics, immunology)
- Swine
- Vaccination
- Vaccines, Synthetic
- Viral Proteins
(pharmacology)
- Viral Vaccines
(administration & dosage, immunology)
- Virus Replication
(immunology)
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