title: Modulation of Potassium Channels Inhibits Bunyavirus Infection.
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.
authors.affiliation: From the School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT.
authors.forename: Samantha
authors.initials: S
authors.lastname: Hover
authors.affiliation: School of Life Sciences, University of Nottingham, Nottingham NG7 2UH.
authors.forename: Barnabas
authors.initials: B
authors.lastname: King
authors.affiliation: From the School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT.
authors.forename: Bradley
authors.initials: B
authors.lastname: Hall
authors.affiliation: From the School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT.
authors.forename: Eleni-Anna
authors.initials: EA
authors.lastname: Loundras
authors.affiliation: From the School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT.
authors.forename: Hussah
authors.initials: H
authors.lastname: Taqi
authors.affiliation: Veterinary Medicine and Science, University of Nottingham, Nottingham NG7 2RD.
authors.forename: Janet
authors.initials: J
authors.lastname: Daly
authors.affiliation: School of Pharmacy, University of Reading, Reading RG6 6AP, and.
authors.forename: Mark
authors.initials: M
authors.lastname: Dallas
authors.affiliation: From the School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT.
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Scotland, Glasgow G61 1QH, United Kingdom.
authors.forename: Esther
authors.initials: E
authors.lastname: Schnettler
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Scotland, Glasgow G61 1QH, United Kingdom.
authors.forename: Clive
authors.initials: C
authors.lastname: McKimmie
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Scotland, Glasgow G61 1QH, United Kingdom.
authors.forename: Alain
authors.initials: A
authors.lastname: Kohl
authors.affiliation: From the School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, J.N.Barr@leeds.ac.uk.
authors.forename: John N
authors.initials: JN
authors.lastname: Barr
authors.affiliation: From the School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, J.Mankouri@leeds.ac.uk.
authors.forename: Jamel
authors.initials: J
authors.lastname: Mankouri
mesh_terms: D000330:Aedes; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002042:Bunyamwera virus / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D002044:Bunyaviridae Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002522:Chlorocebus aethiops; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000187:drug effects*; D006801:Humans; D008647:Mesocricetus; D016855:Nairovirus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D016851:Orthobunyavirus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014709:Vero Cells; D016662:Virus Integration / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C109137:KCNK1 protein, human; C000608774:KCNK7 protein, human; C498655:KCNK9 protein, human; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1
keywords: antiviral agent; ion channel; negative-strand RNA virus; pathogenesis; potassium channel