title: In vitro surrogate models to aid in the development of antivirals for the containment of foot-and-mouth disease outbreaks.
abstract: Foot-and-mouth disease virus (FMDV) is a highly pathogenic member of the genus Aphthovirus (family Picornaviridae) that is only to be manipulated in high-containment facilities, thus complicating research on and discovery of antiviral strategies against the virus. Bovine rhinitis B virus (BRBV) and equine rhinitis A virus (ERAV), phylogenetically most closely related to FMDV, were explored as surrogates for FMDV in antiviral studies. Although no efficient cell culture system has been reported so far for BRBV, we demonstrate that infection of primary bovine kidney cells resulted in an extensive but rather poorly-reproducible induction of cytopathic effect (CPE). Madin-Darby bovine kidney cells on the other hand supported viral replication in the absence of CPE. Antiviral tests were developed for ERAV in Vero A cells employing a viral RNA-reduction assay and CPE-reduction assay; the latter having a Z' factor of 0.83±0.07. The BRBV and ERAV models were next used to assess the anti-aphthovirus activity of two broad-spectrum antiviral agents 2'-C-methylcytidine (2CMC) and ribavirin, as well as of the enterovirus-specific inhibitor enviroxime. The effects of the three compounds in the CPE-reduction (ERAV) and viral RNA-reduction assays (BRBV and ERAV) were comparable. Akin to 2CMC, compound A, a recently-discovered non-nucleoside pan-serotype FMDV inhibitor, also inhibited the replication of both BRBV and ERAV, whereas enviroxime was devoid of activity. The BRBV and ERAV surrogate models reported here can be manipulated in BSL-2 laboratories and may facilitate studies to unravel the mechanism of action of novel FMDV inhibitors.
authors.affiliation: Okapi Sciences NV, Ambachtenlaan 1, 3001 Heverlee, Belgium.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Osiceanu
authors.affiliation: Okapi Sciences NV, Ambachtenlaan 1, 3001 Heverlee, Belgium.
authors.forename: Lyre Espada
authors.initials: LE
authors.lastname: Murao
authors.affiliation: Okapi Sciences NV, Ambachtenlaan 1, 3001 Heverlee, Belgium.
authors.forename: Denny
authors.initials: D
authors.lastname: Kollanur
authors.affiliation: Okapi Sciences NV, Ambachtenlaan 1, 3001 Heverlee, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Swinnen
authors.affiliation: Unit of Vesicular and Exotic Diseases, Virology Department, CODA-CERVA, Veterinary and Agrochemical Research Centre, Groeselenberg 99, 1180 Brussel, Belgium.
authors.forename: Annebel R
authors.initials: AR
authors.lastname: De Vleeschauwer
authors.affiliation: Unit of Vesicular and Exotic Diseases, Virology Department, CODA-CERVA, Veterinary and Agrochemical Research Centre, Groeselenberg 99, 1180 Brussel, Belgium.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefebvre
authors.affiliation: Unit of Vesicular and Exotic Diseases, Virology Department, CODA-CERVA, Veterinary and Agrochemical Research Centre, Groeselenberg 99, 1180 Brussel, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: De Clercq
authors.affiliation: Okapi Sciences NV, Ambachtenlaan 1, 3001 Heverlee, Belgium; Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven (KU Leuven), 3000 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Okapi Sciences NV, Ambachtenlaan 1, 3001 Heverlee, Belgium. Electronic address: nesya.goris@okapi-sciences.com.
authors.forename: Nesya
authors.initials: N
authors.lastname: Goris
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D005537:Aphthovirus / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D002522:Chlorocebus aethiops; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D005536:Foot-and-Mouth Disease / Q000188:drug therapy; D008962:Models, Theoretical; D010091:Oximes; D012367:RNA, Viral / Q000032:analysis; D012254:Ribavirin / Q000494:pharmacology; D013449:Sulfonamides; D014776:Virus Cultivation / Q000379:methods; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D010091:Oximes; D012367:RNA, Viral; D013449:Sulfonamides; C513402:2'-C-methylcytidine; D012254:Ribavirin; D003562:Cytidine; C021595:viroxime
keywords: Antivirals; Aphthovirus; FMDV; Surrogate model