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Title: Constitutively active IRF7/IRF3 fusion protein completely protects swine against Foot-and-Mouth Disease

Author
item RAMIREZ-CARVAJAL, LISBETH - Oak Ridge Institute For Science And Education (ORISE)
item DIAZ-SAN SEGUNDO, FAYNA - University Of Connecticut
item RAMIREZ-MEDINA, ELIZABETH - Oak Ridge Institute For Science And Education (ORISE)
item Rodriguez, Luis
item De Los Santos, Teresa

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/12/2016
Publication Date: 7/27/2016
Citation: Ramirez-Carvajal, L., Diaz-San Segundo, F., Ramirez-Medina, E., Rodriguez, L.L., De Los Santos, T.B. 2016. Constitutively active IRF7/IRF3 fusion protein completely protects swine against Foot-and-Mouth Disease. Journal of Virology. 90:8809-8821. doi: 10.1128/JVI.00800-16.

Interpretive Summary: Foot-and-mouth disease virus (FMDV) causes a fast spreading disease that affects farm animals resulting in economically and socially devastating consequences. Our study shows that inoculation with a constitutively active transcription factor, namely a fusion protein of porcine interferon (IFN) regulatory factors (IRF) 7 and 3, delivered by an adenovirus vector [Ad5-poIRF7/3(5D)] is a new effective treatment to prevent FMD in swine. Animals pre-treated with Ad5-poIRF7/3(5D) one day before being exposed to FMDV are completely protected from viral replication and clinical disease manifestation. We found that after Ad5-poIF7/3(5D) administration, a dynamic interplay between different components of pig’s immune defenses allows potent antiviral effects. Noteworthy, Ad5- poIRF7/3(5D) protective doses are lower than those reported previously with similar approaches but using Ad5 vectors delivering type I, II or III IFN, resulting in an economically appealing strategy to counteract FMD.

Technical Abstract: Foot-and-mouth disease (FMD) remains one of the most devastating livestock diseases around the world. Several serotype specific vaccine formulations exist but require about 5-7 days to induce protective immunity. Our previous studies have shown that a constitutively active fusion protein of porcine interferon (IFN) regulatory factor (IRF) 7 and 3 [IRF7/3(5D)] strongly induced type I IFN and antiviral genes in vitro and prevented mortality in a FMD mouse model when delivered with a replication defective adenoviral vector [Ad5-poIRF7/3(5D)]. Here, we demonstrate that pigs treated with 108, 109, or 1010 PFU of Ad5-poIRF7/3(5D) 24 h before FMDV challenge, were fully protected from FMD clinical signs, developed no viremia, virus shedding, or antibodies against FMDV nonstructural proteins. Consistently, pigs treated with Ad5-poIRF7/3(5D) had higher levels of IFN and antiviral activity in serum, and upregulated expression of several IFN stimulated genes in peripheral blood mononuclear cells. Importantly, treatment of porcine cultured cells with Ad5-poIRF7/3(5D) inhibited all 7 FMDV serotypes. In vitro experiments using cultured embryonic fibroblast derived from IFN receptor knockout mice suggested that the antiviral response induced by Ad5-poIRF7/3(5D), was dependent on type I and type III IFN pathway, however experiments with mice demonstrated that functional type I IFN pathway mediates Ad5-poIRF7/3(5D) protection conferred in vivo. Our studies demonstrate that inoculation with Ad5-poIRF7/3(5D) completely protects swine against FMD by inducing a strong type I IFN response, and highlights its potential application to rapidly and effectively prevent FMDV replication and dissemination