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Open AccessArticle

Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication

1
The State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China
2
Department of Microbiology, University of Veterinary and Animal Sciences, Lahore 54000, Pakistan
3
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China
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Department of Molecular Medicine, University of Padua, 35121 Padua, Italy
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Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
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Key Laboratory of Development of Veterinary Diagnostic Products, Key Laboratory of Ruminant Bio-Products of Ministry of Agriculture and Rural Affairs, Wuhan 430070, China
7
Hubei International Scientific and Technological Cooperation Base of Veterinary Epidemiology, International Research Center for Animal Disease, Ministry of Science and Technology of the People’s Republic of China, Wuhan 430070, China
*
Authors to whom correspondence should be addressed.
Microorganisms 2020, 8(3), 409; https://doi.org/10.3390/microorganisms8030409
Received: 19 February 2020 / Revised: 11 March 2020 / Accepted: 12 March 2020 / Published: 13 March 2020
(This article belongs to the Special Issue Herpesviruses: Virus-Host Interaction)
Bovine herpesvirus1 (BoHV-1) is a major bovine pathogen. Despite several vaccines being available to prevent viral infection, outbreaks are frequent and cause important economic consequences worldwide. The development of new antiviral drugs is therefore highly desirable. In this context, viral genome replication represents a potential target for therapeutic intervention. BoHV-1 genome is a dsDNA molecule whose replication takes place in the nuclei of infected cells and is mediated by a viral encoded DNA polymerase holoenzyme. Here, we studied the physical interaction and subcellular localization of BoHV-1 DNA polymerase subunits in cells for the first time. By means of co-immunoprecipitation and confocal laser scanning microscopy (CLSM) experiments, we could show that the processivity factor of the DNA polymerase pUL42 is capable of being autonomously transported into the nucleus, whereas the catalytic subunit pUL30 is not. Accordingly, a putative classic NLS (cNLS) was identified on pUL42 but not on pUL30. Importantly, both proteins could interact in the absence of other viral proteins and their co-expression resulted in accumulation of UL30 to the cell nucleus. Treatment of cells with Ivermectin, an anti-parasitic drug which has been recently identified as an inhibitor of importin α/β-dependent nuclear transport, reduced UL42 nuclear import and specifically reduced BoHV-1 replication in a dose-dependent manner, while virus attachment and entry into cells were not affected. Therefore, this study provides a new option of antiviral therapy for BoHV-1 infection with Ivermectin. View Full-Text
Keywords: BoHV-1; nucleocytoplasmic shuttling; Ivermectin; antiviral; NLS; DNA polymerase holoenzyme; pUL30; pUL42 BoHV-1; nucleocytoplasmic shuttling; Ivermectin; antiviral; NLS; DNA polymerase holoenzyme; pUL30; pUL42
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MDPI and ACS Style

Raza, S.; Shahin, F.; Zhai, W.; Li, H.; Alvisi, G.; Yang, K.; Chen, X.; Chen, Y.; Chen, J.; Hu, C.; Chen, H.; Guo, A. Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication. Microorganisms 2020, 8, 409.

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