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Redirecting Imipramine against Bluetongue Virus Infection: Insights from a Genome-wide Haploid Screening Study John, Lijo; Vernersson, Caroline; Kwon, Hyesoo; Elling, Ulrich; Penninger, Josef; Mirazimi, Ali

Abstract

Bluetongue virus (BTV), an arbovirus of ruminants, is a causative agent of numerous epidemics around the world. Due to the emergence of novel reassortant BTV strains and new outbreaks, there is an unmet need for efficacious antivirals. In this study, we used an improved haploid screening platform to identify the relevant host factors for BTV infection. Our screening tool identified and validated the host factor Niemann–Pick C1 (NPC1), a lysosomal membrane protein that is involved in lysosomal cholesterol transport, as a critical factor in BTV infection. This finding prompted us to investigate the possibility of testing imipramine, an antidepressant drug known to inhibit NPC1 function by interfering with intracellular cholesterol trafficking. In this study, we evaluated the sensitivity of BTV to imipramine using in vitro assays. Our results demonstrate that imipramine pretreatment inhibited in vitro replication and progeny release of BTV-4, BTV-8, and BTV-16. Collectively, our findings highlight the importance of NPC1 for BTV infection and recommend the reprofiling of imipramine as a potential antiviral drug against BTV.

Item Metadata

Title
Redirecting Imipramine against Bluetongue Virus Infection: Insights from a Genome-wide Haploid Screening Study
Creator
John, Lijo; Vernersson, Caroline; Kwon, Hyesoo; Elling, Ulrich; Penninger, Josef; Mirazimi, Ali
Contributor
University of British Columbia. Life Sciences Institute
Publisher
Multidisciplinary Digital Publishing Institute
Date Issued
2022-05-22
Description
Bluetongue virus (BTV), an arbovirus of ruminants, is a causative agent of numerous epidemics around the world. Due to the emergence of novel reassortant BTV strains and new outbreaks, there is an unmet need for efficacious antivirals. In this study, we used an improved haploid screening platform to identify the relevant host factors for BTV infection. Our screening tool identified and validated the host factor Niemann–Pick C1 (NPC1), a lysosomal membrane protein that is involved in lysosomal cholesterol transport, as a critical factor in BTV infection. This finding prompted us to investigate the possibility of testing imipramine, an antidepressant drug known to inhibit NPC1 function by interfering with intracellular cholesterol trafficking. In this study, we evaluated the sensitivity of BTV to imipramine using in vitro assays. Our results demonstrate that imipramine pretreatment inhibited in vitro replication and progeny release of BTV-4, BTV-8, and BTV-16. Collectively, our findings highlight the importance of NPC1 for BTV infection and recommend the reprofiling of imipramine as a potential antiviral drug against BTV.
Subject
bluetongue virus; haploid screening; imipramine; Niemann–Pick C1; BTV serotypes
Genre
Article
Type
Text
Language
eng
Date Available
2022-08-10
Provider
Vancouver : University of British Columbia Library
Rights
CC BY 4.0
DOI
10.14288/1.0416752
URI
http://hdl.handle.net/2429/82313
Affiliation
Medicine, Faculty of; Non UBC; Medical Genetics, Department of
Citation
Pathogens 11 (5): 602 (2022)
Publisher DOI
10.3390/pathogens11050602
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher
Rights URI
https://creativecommons.org/licenses/by/4.0/
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CC BY 4.0