Modulation of potassium channels inhibits bunyavirus infection

Hover, Samantha; King, Barnabas; Hall, Bradley; Loundras, Eleni-Anna; Taqi, Hussah; Daly, Janet M.; Dallas, Mark; Peers, Chris; Schnettler, Esther; McKimmie, Clive; Kohl, Alain; Barr, John N.; Mankouri, Jamel

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, two-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.

Citation

Hover, S., King, B., Hall, B., Loundras, E., Taqi, H., Daly, J. M., …Mankouri, J. (2016). Modulation of potassium channels inhibits bunyavirus infection. Journal of Biological Chemistry, 291(7), 3411-3422. https://doi.org/10.1074/jbc.M115.692673

• Journal Article Type: Article
• Acceptance Date: Dec 16, 2015
• Online Publication Date: Dec 16, 2015
• Publication Date: Feb 12, 2016
• Deposit Date: Jan 4, 2016
• Publicly Available Date: Jan 4, 2016
• Journal: Journal of Biological Chemistry
• Print ISSN: 0021-9258
• Electronic ISSN: 1083-351X
• Publisher: American Society for Biochemistry and Molecular Biology
• Peer Reviewed: Peer Reviewed
• Volume: 291
• Issue: 7
• Pages: 3411-3422
• DOI: https://doi.org/10.1074/jbc.M115.692673
• Public URL: https://nottingham-repository.worktribe.com/output/769224
• Publisher URL: https://www.jbc.org/content/291/7/3411
• Additional Information: This research was originally published in Journal of Biological Chemistry. Samantha Hover, Barnabas King, Bradley Hall, Eleni-Anna Loundras, Hussah Taqi, Janet Daly, Mark Dallas, Chris Peers, Esther Schnettler, Clive McKimmie, Alain Kohl, John N. Barr, and Jamel Mankouri: ; Modulation of potassium channels inhibits bunyavirus infection. Journal of Biological Chemistry. Papers in Press 16 December 2015. jbc.M115.692673 © the American Society for Biochemistry and Molecular Biology