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

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 genom...

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Autores principales: Raza, Sohail, Shahin, Farzana, Zhai, Wenjun, Li, Hanxiong, Alvisi, Gualtiero, Yang, Kui, Chen, Xi, Chen, Yingyu, Chen, Jianguo, Hu, Changmin, Chen, Huanchun, Guo, Aizhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143239/
https://www.ncbi.nlm.nih.gov/pubmed/32183205
http://dx.doi.org/10.3390/microorganisms8030409
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author Raza, Sohail
Shahin, Farzana
Zhai, Wenjun
Li, Hanxiong
Alvisi, Gualtiero
Yang, Kui
Chen, Xi
Chen, Yingyu
Chen, Jianguo
Hu, Changmin
Chen, Huanchun
Guo, Aizhen
author_facet Raza, Sohail
Shahin, Farzana
Zhai, Wenjun
Li, Hanxiong
Alvisi, Gualtiero
Yang, Kui
Chen, Xi
Chen, Yingyu
Chen, Jianguo
Hu, Changmin
Chen, Huanchun
Guo, Aizhen
author_sort Raza, Sohail
collection PubMed
description 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.
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spelling pubmed-71432392020-04-14 Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication Raza, Sohail Shahin, Farzana Zhai, Wenjun Li, Hanxiong Alvisi, Gualtiero Yang, Kui Chen, Xi Chen, Yingyu Chen, Jianguo Hu, Changmin Chen, Huanchun Guo, Aizhen Microorganisms Article 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. MDPI 2020-03-13 /pmc/articles/PMC7143239/ /pubmed/32183205 http://dx.doi.org/10.3390/microorganisms8030409 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Raza, Sohail
Shahin, Farzana
Zhai, Wenjun
Li, Hanxiong
Alvisi, Gualtiero
Yang, Kui
Chen, Xi
Chen, Yingyu
Chen, Jianguo
Hu, Changmin
Chen, Huanchun
Guo, Aizhen
Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication
title Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication
title_full Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication
title_fullStr Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication
title_full_unstemmed Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication
title_short Ivermectin Inhibits Bovine Herpesvirus 1 DNA Polymerase Nuclear Import and Interferes With Viral Replication
title_sort ivermectin inhibits bovine herpesvirus 1 dna polymerase nuclear import and interferes with viral replication
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143239/
https://www.ncbi.nlm.nih.gov/pubmed/32183205
http://dx.doi.org/10.3390/microorganisms8030409
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