Modulation of potassium channels inhibits bunyavirus infection

Hover, S., King, B., Hall, B., Loundras, E.-A., Taqi, H., Daly, J., Dallas, M. ORCID: https://orcid.org/0000-0002-5190-0522, Peers, C., Schnettler, E., McKimmie, C., Kohl, A., Barr, J. N. and Mankouri, J. (2016) Modulation of potassium channels inhibits bunyavirus infection. The Journal of Biological Chemistry, 291 (7). pp. 3411-3422. ISSN 1083-351X doi: 10.1074/jbc.M115.692673

Abstract/Summary

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	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/49365
Identification Number/DOI	10.1074/jbc.M115.692673
Refereed	Yes
Divisions	Interdisciplinary Research Centres (IDRCs) > Centre for Integrative Neuroscience and Neurodynamics (CINN) Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	American Society for Biochemistry and Molecular Biology
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