title: Novel antiviral therapeutics to control foot-and-mouth disease.
abstract: Foot-and-mouth disease virus (FMDV) causes a highly contagious disease of cloven-hoofed animals. Vaccines require ∼7 days to induce protection; thus, before this time, vaccinated animals are still susceptible to the disease. Our group has previously shown that swine inoculated with 1×10(11) focus forming units (FFU) of a replication-defective human adenovirus containing the gene for porcine interferon alpha (Adt-pIFN-α) are sterilely protected from FMDV serotypes A24, O1 Manisa, or Asia 1 when the animals are challenged 1 day postadministration, and protection can last for 3-5 days. Polyriboinosinic-polyribocytidylic acid stabilized with poly-l-lysine and carboxymethyl cellulose (poly ICLC) is a synthetic double-stranded RNA that is a viral mimic and activates multiple innate immune pathways through interaction with toll-like receptor 3 and MDA-5. It is a potent inducer of IFNs. In this study, we initially examined the effect of poly IC and IFN-α on FMDV replication and gene induction in cell culture. Poly ICLC alone or combined with Adt-pIFN-α was then evaluated for its therapeutic efficacy in swine against intradermal challenge with FMDV A24, 1 day post-treatment. Groups of swine were subcutaneously inoculated either with poly ICLC alone (4 or 8 mg) or in combination with different doses of Adt-pIFN-α (2.5×10(9), 1×10(9), or 2.5×10(8) FFU). While different degrees of protection were achieved in all the treated animals, a dose of 8 mg of poly ICLC alone or combined with 1×10(9) FFU of Adt-pIFN-α was sufficient to sterilely protect swine when challenged 24 h later with FMDV A24. IFN-stimulated gene (ISG) expression in peripheral blood mononuclear cells at 1 day post-treatment was broader and higher in protected animals than in nonprotected animals. These data indicate that poly ICLC is a potent stimulator of IFN and ISGs in swine and at an adequate dose is sufficient to induce complete protection against FMD.
authors.affiliation: Plum Island Animal Disease Center, North Atlantic Area, Agricultural Research Service, U.S. Department of Agriculture, Greenport, New York 11944, USA.
authors.forename: Camila C
authors.initials: CC
authors.lastname: Dias
authors.forename: Mauro P
authors.initials: MP
authors.lastname: Moraes
authors.forename: Marcelo
authors.initials: M
authors.lastname: Weiss
authors.forename: Fayna
authors.initials: F
authors.lastname: Diaz-San Segundo
authors.forename: Eva
authors.initials: E
authors.lastname: Perez-Martin
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.forename: Teresa
authors.initials: T
authors.lastname: de los Santos
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Grubman
mesh_terms: D000256:Adenoviridae; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001691:Biological Therapy / Q000379:methods*; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002478:Cells, Cultured; D005536:Foot-and-Mouth Disease / Q000276:immunology / Q000628:therapy*; D029544:Foot-and-Mouth Disease Virus; D005822:Genetic Vectors; D006801:Humans; D007113:Immunity, Innate; D007369:Interferon Inducers / Q000008:administration & dosage*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D011070:Poly I-C / Q000008:administration & dosage*; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013552:Swine; D019076:Transgenes / Q000235:genetics; D014779:Virus Replication
chemical_list: D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; D007369:Interferon Inducers; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C