Modulation of potassium channels inhibits bunyavirus infection

Hover, S. et al. (2016) Modulation of potassium channels inhibits bunyavirus infection. Journal of Biological Chemistry, 291(7), pp. 3411-3422. (doi:10.1074/jbc.M115.692673) (PMID:26677217) (PMCID:PMC4751384)

[img]
Preview
Text
114511.pdf - Published Version
Available under License Creative Commons Attribution.

2MB

Abstract

Bunyaviruses are considered to be emerging pathogens facilitated by the segmented nature of their genome that allows reassortment between different species to generate novel viruses with altered pathogenicity. Bunyaviruses are transmitted via a diverse range of arthropod vectors, as well as rodents, and have established a global disease range with massive importance in healthcare, animal welfare and economics. There are no vaccines or anti-viral therapies available to treat human bunyavirus infections and so development of new anti-viral strategies is urgently required. Bunyamwera virus (BUNV; genus Orthobunyavirus) is the model bunyavirus, sharing aspects of its molecular and cellular biology with all Bunyaviridae family members. Here, we show for the first time that BUNV activates and requires cellular potassium (K+) channels to infect cells. Time of addition assays using K+ channel modulating agents demonstrated that K+ channel function is critical to events shortly after virus entry but prior to viral RNA synthesis/replication. A similar K+ channel dependence was identified for other bunyaviruses namely Schmallenberg virus (Orthobunyavirus) as well as the more distantly related Hazara virus (Nairovirus). Using a rational pharmacological screening regimen, twin-pore domain K+ channels (K2P) were identified as the K+ channel family mediating BUNV K+ channel dependence. As several K2P channel modulators are currently in clinical use, our work suggests they may represent a new and safe drug class for the treatment of potentially lethal bunyavirus disease.

Item Type:Articles
Additional Information:Royal Society University Research Fellow (grant number UF100419 ). The confocal microscope used for imaging was funded by a Royal Society equipment grant (grant number RG110306
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Schnettler, Dr Esther and McKimmie, Dr Clive and Kohl, Professor Alain
Authors: Hover, S., King, B., Hall, B., Loundras, E.-A., Taqi, H., Daly, J., Dallas, M., Peers, C., Schnettler, E., McKimmie, C., Kohl, A., Barr, J. N., and Mankouri, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:16 December 2015
Copyright Holders:Copyright © 2016 The American Society for Biochemistry and Molecular Biology, Inc.
First Published:First published in Journal of Biological Chemistry 291(7): 3411-3422
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record