Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture

PLOS ONE, Dec 2019

Parrot bornavirus 4 is an etiological agent of proventricular dilatation disease, a fatal neurologic and gastrointestinal disease of psittacines and other birds. We tested the ability of ribavirin, an antiviral nucleoside analog with antiviral activity against a range of RNA and DNA viruses, to inhibit parrot bornavirus 4 replication in duck embryonic fibroblast cells. Two analytical methods that evaluate different products of viral replication, indirect immunocytochemistry for viral specific nucleoprotein and qRT-PCR for viral specific phosphoprotein gene mRNA, were used. Ribavirin at concentrations between 2.5 and 25 μg/mL inhibited parrot bornavirus 4 replication, decreasing viral mRNA and viral protein load, in infected duck embryonic fibroblast cells. The addition of guanosine diminished the antiviral activity of ribavirin suggesting that one possible mechanism of action against parrot bornavirus 4 may likely be through inosine monophosphate dehydrogenase inhibition. This study demonstrates parrot bornavirus 4 susceptibility to ribavirin in cell culture.

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Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture

July Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture Jeffrey M. B. Musser 0 1 2 J. Jill Heatley 0 1 2 Anastasia V. Koinis 0 1 2 Paulette F. Suchodolski 0 1 2 Jianhua Guo 0 1 2 Paulina Escandon 0 1 2 Ian R. Tizard 0 1 2 0 1 Schubot Exotic Bird Health Center, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America, 2 Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America, 3 Zoological Medicine, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, Texas, United States of America, 4 Morris Animal Foundation Veterinary Student Scholar, College of Veterinary Medicine, Texas A&M University, College Station , Texas , United States of America 1 Funding: This work was supported by Schubot Exotic Bird Health Center (JMBM, JJH) and Morris Animal Foundation Veterinary Student Scholar , AVK 2 Editor: Kylene Kehn-Hall, George Mason University , UNITED STATES Parrot bornavirus 4 is an etiological agent of proventricular dilatation disease, a fatal neurologic and gastrointestinal disease of psittacines and other birds. We tested the ability of ribavirin, an antiviral nucleoside analog with antiviral activity against a range of RNA and DNA viruses, to inhibit parrot bornavirus 4 replication in duck embryonic fibroblast cells. Two analytical methods that evaluate different products of viral replication, indirect immunocytochemistry for viral specific nucleoprotein and qRT-PCR for viral specific phosphoprotein gene mRNA, were used. Ribavirin at concentrations between 2.5 and 25 μg/mL inhibited parrot bornavirus 4 replication, decreasing viral mRNA and viral protein load, in infected duck embryonic fibroblast cells. The addition of guanosine diminished the antiviral activity of ribavirin suggesting that one possible mechanism of action against parrot bornavirus 4 may likely be through inosine monophosphate dehydrogenase inhibition. This study demonstrates parrot bornavirus 4 susceptibility to ribavirin in cell culture. - Competing Interests: The authors have declared that no competing interests exist. Parrot bornavirus 4 (PaBV-4) is an enveloped, non-segmented, negative sense RNA virus in the family Bornaviridae. Recent phylogenetic analysis of viruses within the family Bornaviridae, which includes the formerly named Avian Bornavirus, resulted in new nomenclature and taxonomic reorganization of Bornaviridae into 5 species: Mammalian 1 bornavirus, Psittaciform 1 bornavirus, Passeriform 1 bornavirus, Passeriform 2 bornavirus, and Waterbird 1 bornavirus [1]. Epidemiological and experimental results support that PaBV-1, -2, -3, -4, -7, all members of the species Psittaciform 1 bornavirus, are etiological agents of proventricular dilatation disease (PDD), a fatal neurologic and gastrointestinal syndrome of psittacines and other birds [2–4]. In infected birds, the virus has a tropism for the brain and nervous tissue of psittacines [5–10], but can be found in a majority of tissues including kidney, medullary cords of the adrenal gland, heart, spleen, liver, lungs, pancreas, testes and ovary [7–10]. Bornaviruses are noncytopathic in cell culture [4,9]. Presently, there is no proven efficacious treatment in birds against PaBV infections or for reducing viral shedding. INF-α inhibits virus infection and viral load of the virus in quail cell culture [11]. Non-steroidal anti-inflammatory drugs, to inhibit or reduce the inflammatory reaction, are currently the principal treatment for PDD [12]. Celecoxid, meloxicam, and cyclosporine are used clinically and experimentally with mixed results [12,13]. These drugs are mainly symptomatic treatments of clinical PDD and their use may be contraindicated. In cockatiels experimentally infected with PaBV-4 and treated with meloxicam, severe weight loss and depression was noted and upon necropsy and testing, there was pathological evidence of PDD and increased PaBV-4 dissemination [14]. Ribavirin (1-ß-D-ribofuranosyl- 1,2,4-Triazole-3-carboxamide), a broad-spectrum antiviral nucleoside analog [15], has in vitro and in vivo antiviral activity against a broad range of RNA and DNA viruses. In human clinical practice, ribavirin is used, alone or in combination with other drugs, in the treatment of infections with hepatitis C virus, respiratory syncytial virus, and Lassa fever virus [16–21]. Experimentally in veterinary species, ribavirin shows antiviral activity against foot-and-mouth disease virus [22], infectious salmon anemia virus [23], viral hemorrhagic septicemia virus [24], and canine parainfluenza virus [25]. In mice, combination treatment with ribavirin and baicalein provides better protection against influenza virus as compared to the individual chemicals alone [26]. With specific regard to the family Bornaviridae, ribavirin, at concentrations ranging from 1 to 10 μg/mL, inhibi (...truncated)


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Jeffrey M. B. Musser, J. Jill Heatley, Anastasia V. Koinis, Paulette F. Suchodolski, Jianhua Guo, Paulina Escandon, Ian R. Tizard. Ribavirin Inhibits Parrot Bornavirus 4 Replication in Cell Culture, PLOS ONE, 2015, Volume 10, Issue 7, DOI: 10.1371/journal.pone.0134080