Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) in vitro
Virus Research, doi:10.1016/j.virusres.2021.198384
In vitro testing Bovine coronavirus Bovine viral diarrhea virus Bovine respiratory syncytial virus Bovine parainfluenza type 3 virus Bovine herpesvirus type 1 A B S T R A C T Bovine respiratory disease (BRD) complex is an important viral infection that causes huge economic losses in cattle herds worldwide. However, there is no directly effective antiviral drug application against respiratory viral pathogens; generally, the metaphylactic antibacterial drug applications are used for BRD. Ivermectin (IVM) is currently used as a broad-spectrum anti-parasitic agent both for veterinary and human medicine on some occasions. Moreover, since it is identified as an inhibitor for importin α/β-mediated nuclear localization signal (NLS), IVM is also reported to have antiviral potential against several RNA and DNA viruses. Since therapeutic use of IVM in COVID-19 cases has recently been postulated, the potential antiviral activity of IVM against bovine respiratory viruses including BRSV, BPIV-3, BoHV-1, BCoV and BVDV are evaluated in this study. For these purposes, virus titration assay was used to evaluate titers in viral harvest from infected cells treated with noncytotoxic IVM concentrations (1, 2.5 and 5 μM) and compared to titers from non-treated infected cells. This study indicated that IVM inhibits the replication of BCoV, BVDV, BRSV, BPIV-3 and BoHV-1 in a dose-dependent manner in vitro as well as number of extracellular infectious virions. In addition, it was demonstrated that IVM has no clear effect on the attachment and penetration steps of the replication of the studied viruses. Finally, this study shows for the first time that IVM can inhibit infection of BRD-related viral agents namely BCoV, BPIV-3, BVDV, BRSV and BoHV-1 at the concentrations of 2.5 and 5 μM. Consequently, IVM, which is licensed for antiparasitic indications, also deserves to be evaluated as a broad-spectrum antiviral in BRD cases caused by viral pathogens.
Experiment no Target Treatment Viral titers (Log10 TCID 50 )* BRSV BPIV-3 BoHV-1 BCoV BVDV #2 Virus attachment Non-treated 10 6.75 10 7.00 10 5.75 10 4.50 10 5.50 IVM-treated 10 6.75 10 6.75 10 5.50 10 4.50 10 5.50 #3 Virus penetration Non-treated 10 5.50 10 6.50 10 5.75 10 4.75 10 3.50 IVM-treated 10 5.25 10 6.50 10 5.25 10 4.25 10 2.75 * No statistical significance was observed between titers obtained from treated and non-treated experiments of the particular virus species.
Author statement Kadir Yesilbag: Conceptualization, Methodology, Supervising, Writing, Redactions, Funding acquisition. Eda Baldan Toker: Writing-Original draft preparation, Validation, Investigation, Formal analysis Ozer Ates: Resource, Investigation.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10. 1016/j.virusres.2021.198384.
Autio, Pohjanvirta, Holopainen, Rikula, Pentikäinen et al., Etiology of respiratory disease in non-vaccinated, non-medicated calves in rearing herds, Vet. Microbiol, doi:10.1016/j.vetmic.2006.10.001
Azeem, Ashraf, Rasheed, Anjum, Hameed, Evaluation of cytotoxicity and antiviral activity of ivermectin against Newcastle disease virus, Pak. J. Pharm. Sci
Caly, Druce, Catton, Jans, Wagstaff et al., The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antivir. Res. J
Chamorro, Palomares, Bovine respiratory disease vaccination against viral pathogens: modified-live versus inactivated antigen vaccines, intranasal versus parenteral, what is the evidence?, Vet. Clin. North Am. -Food Anim. Pract, doi:10.1016/j.cvfa.2020.03.006
Görlich, Kostka, Kraft, Dingwall, Laskey et al., Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope, Curr. Biol, doi:10.1016/S0960-9822(95)00079-0
Ictv ; Ji, Luo, Zika virus NS5 nuclear accumulation is protective of protein degradation and is required for viral RNA replication, Virology, doi:10.1016/j.virol.2019.10.010
Jones, Chowdhury, Bovine herpesvirus type 1 (BHV-1) is an important cofactor in the bovine respiratory disease complex, Vet. Clin. North Am. -Food Anim. Pract, doi:10.1016/j.cvfa.2010.04.007
Kawashima, Kanda, Murata, Saito, Sugimoto et al., Nuclear Transport of Epstein-Barr Virus DNA Polymerase Is Dependent on the BMRF1 Polymerase Processivity Factor and Molecular Chaperone Hsp90, J. Virol, doi:10.1128/jvi.03428-12
Lee, Lee, Ivermectin inhibits porcine reproductive and respiratory syndrome virus in cultured porcine alveolar macrophages, Arch. Virol, doi:10.1007/s00705-015-2653-2
Lundberg, Pinkham, Baer, Amaya, Narayanan et al., Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication, Antiviral Res, doi:10.1016/j.antiviral.2013.10.004
Lv, Liu, Wang, Dang, Qiu et al., Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo, Antiviral Res, doi:10.1016/j.antiviral.2018.09.010
Mastrangelo, Pezzullo, De Burghgraeve, Kaptein, Pastorino et al., Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: New prospects for an old drug, J. Antimicrob. Chemother, doi:10.1093/jac/dks147
Raza, Shahin, Zhai, Li, Alvisi et al., Ivermectin inhibits bovine herpesvirus 1 DNA polymerase nuclear import and interferes with viral replication, Microorganisms, doi:10.3390/microorganisms8030409
Tay, Fraser, Chan, Moreland, Rathore et al., Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin, Antiviral Res, doi:10.1016/j.antiviral.2013.06.002
Urban-Chmiel, Grooms, Prevention and control of bovine respiratory disease, J. Livest. Sci
Varghese, Kaukinen, Gläsker, Bespalov, Hanski et al., Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses, Antiviral Res, doi:10.1016/j.antiviral.2015.12.012
Wagstaff, Sivakumaran, Heaton, Harrich, Jans, Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochem. J, doi:10.1042/BJ20120150
Wang, Lv, Ji, Wang, Qiu et al., Ivermectin treatment inhibits the replication of Porcine circovirus 2 (PCV2) in vitro and mitigates the impact of viral infection in piglets, Virus Res, doi:10.1016/j.virusres.2019.01.010
Yang, Atkinson, Wang, Lee, Bogoyevitch et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer, Antiviral Res, doi:10.1016/j.antiviral.2020.104760