title: Expression of porcine fusion protein IRF7/3(5D) efficiently controls foot-and-mouth disease virus replication.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: ORISE-Plum Island Animal Disease Center Research Participation Program, Oak Ridge, Tennessee, USA College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, Texas, USA.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Ramírez-Carvajal
authors.affiliation: Plum Island Animal Disease Center, ARS, USDA, Greenport, New York, USA.
authors.forename: Fayna
authors.initials: F
authors.lastname: Díaz-San Segundo
authors.affiliation: Plum Island Animal Disease Center, ARS, USDA, Greenport, New York, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Hickman
authors.affiliation: College of Veterinary Medicine and Biomedical Science, Texas A&M University, College Station, Texas, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Long
authors.affiliation: Plum Island Animal Disease Center, ARS, USDA, Greenport, New York, USA.
authors.forename: James
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Plum Island Animal Disease Center, ARS, USDA, Greenport, New York, USA.
authors.forename: Luis L
authors.initials: LL
authors.lastname: Rodríguez
authors.affiliation: Plum Island Animal Disease Center, ARS, USDA, Greenport, New York, USA teresa.delossantos@ars.usda.gov.
authors.forename: Teresa
authors.initials: T
authors.lastname: de los Santos
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D005536:Foot-and-Mouth Disease / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression / Q000276:immunology; D005822:Genetic Vectors; D006801:Humans; D007369:Interferon Inducers / Q000037:antagonists & inhibitors / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D007370:Interferon Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D013552:Swine; D014611:Vaccination; D014614:Vaccines, Synthetic; D014764:Viral Proteins / Q000494:pharmacology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology
chemical_list: D007369:Interferon Inducers; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; D014764:Viral Proteins; D014765:Viral Vaccines; C067853:B18R protein, Vaccinia virus