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United States Department of Agriculture

Agricultural Research Service

Research Project: Intervention Strategies to Support the Global Control and Eradication of Foot-and-Mouth Disease Virus (Fmdv)

Location: Foreign Animal Disease Research

Title: Expression of porcine fusion protein IRF7/3(5D) efficiently controls foot-and-mouth disease virus replication

Authors
item Ramirez-Carvajal, Lisbeth -
item Long, Charles -
item Zhu, James
item Diaz San Segundo, Fayna
item Rodriguez, Luis
item De Los Santos, Teresa

Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 3, 2014
Publication Date: July 16, 2014
Citation: Ramirez-Carvajal, L., Long, C.R., Zhu, J.J., Diaz San Segundo, F.C., Rodriguez, L.L., De Los Santos, T.B. 2014. Expression of porcine fusion protein IRF7/3(5D) efficiently controls foot-and-mouth disease virus replication. Journal of Virology. 88(19):11140-11153.

Interpretive Summary: Interferons (IFNs) are molecules with characterized antiviral function. Administration of IFNs using a replication defective human adenovirus 5 vector (Ad5), is effective to control Foot-and-Mouth Disease (FMD) in cattle and/or swine, however, high doses of Ad5 are required. In this manuscript, we characterize a new fusion protein as a biotherapeutic strategy against FMD. The fusion protein induces high levels of IFNs, many antiviral genes, and reduced FMDV yield without being toxic to bovine and porcine cell lines. Also, this fusion protein used at low doses, enhanced the antiviral effects of an Ad5 expressing porcine IFN. Our results also suggested that the fusion protein might have antiviral activity that is independent from the antiviral activity induced by IFNs. Testing of the fusion protein in vivo in mice showed high levels of IFNs in sera and fully protected against FMDV replication. This study, for the first time, highlights the antiviral potential of the fusion protein in vitro and in vivo against FMDV.

Technical Abstract: Several studies have demonstrated that administration of type I, II, or III interferons (IFN) delivered using a replication defective human adenovirus 5 (Ad5) vector is effective to control Foot-and-Mouth Disease (FMD) in cattle and swine during experimental infections. However, high doses are required to achieve protection. In this manuscript, we characterize the functional properties of a porcine fusion protein (poIRF7/3(5D) as a biotherapeutic and enhancer of IFNs against FMD virus (FMDV). We showed that poIRF7/3(5D) is a potent inducer of IFN alpha, beta, and omega but not Type III IFN (IL28B), without inducing cytotoxicity. Expression of poIRF7/3(5D) significantly and steadily reduced FMDV viral titers by up to 6 log10 in bovine and swine cell lines. An Ad5-poIRF7/3(5D) enhanced the antiviral effects of Ad5-poIFN beta when used at low multiplicity of infection. There was no detectable antiviral activity in the supernatants of Ad5-poIRF7/3(5D) transduced cells treated with IFN receptor inhibitor (B18R)combined with an anti-IFN alpha antibody. However, several transcripts with known antiviral function, including type I IFNs, were still highly up-regulated (ranging from 8- 565 fold increase) by poIRF7/3(5D) in the presence of B18R. Furthermore, mice treated with Ad5-poIRF7/3(5D) showed antiviral activity in sera that was associated with high induction of IFN alpha (100 fold) and beta (2 fold) and resulted in complete protection against FMDV challenge. This study, highlights for the first time, the antiviral potential of Ad5-poIRF7/3(5D) in vitro and in vivo against FMDV when administrated alone or in combination with Ad5-poIFN beta.

Last Modified: 10/31/2014
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