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.

Viral dependence on cellular ion channels – an emerging anti-viral target?

“…BUNV was found to activate K + channels during the initial 6 h of virus infection [13], and furthermore, K + channel inhibition during this life cycle stage was shown to be detrimental to BUNV, identifying a requirement of K + channel functionality during events shortly after virus entry but prior to viral RNA synthesis [13]. This early time frame includes post-entry endosomal trafficking, virus-host membrane fusion and ribonucleoprotein release prior to the formation of 'viral factories' at the Golgi (K + channels are likely required at the plasma membrane or within endosomal compartments; see Fig.…”

“…2b). Using a rational panel of more specific K + channel pharmacological modulators, twopore K + channels (K 2P ) were implicated as the channel family required by BUNV [13]. Importantly, this requirement for K + channel function was shared with other bunyaviruses, including Schmallenberg virus and Hazara virus, implicating it as a potential virus-host interaction utilized by many bunyavirus family members [13].…”

“…Using a rational panel of more specific K + channel pharmacological modulators, twopore K + channels (K 2P ) were implicated as the channel family required by BUNV [13]. Importantly, this requirement for K + channel function was shared with other bunyaviruses, including Schmallenberg virus and Hazara virus, implicating it as a potential virus-host interaction utilized by many bunyavirus family members [13]. Since the cellular function of K 2P channels are not constrained to the plasma membrane, it is interesting to speculate that an endosomal function of K 2P channels dictates their role in bunyavirus infection, although the mechanism(s) of this relationship require further investigation.…”

Selectivity filter instability dominates the low intrinsic activity of the TWIK-1 K2P K+ Channel

“…One possibility may be related to the dynamic nature of TWIK-1 ion selectivity and that significant levels of TWIK-1 channels have been reported within endosomes where the unusual ionic environment and pH may modulate its functional properties (15,18,31). Also, the K + concentrations within intracellular endosomes have been reported to be highly dynamic and proposed to play a role in the control of viral trafficking (32); in addition K2P channels are thought to play a key role in this process, though a specific role for TWIK-1 remains to be determined (33). Nevertheless, the unique biophysical properties we have identified in this study will clearly aid future functional and cellular studies of this enigmatic ion channel.…”

A requirement for Potassium and Calcium Channels during the Endosomal Trafficking of Polyomavirus Virions

“…Emerging studies suggest that the current description of virus entry processes involving acidification alone are too simplistic and that the accumulation of other ions including K + and Ca 2+ influence virus trafficking (38–43). In the context of PyV infection, Ca 2+ ions have been shown to affect the structure and organisation of virus particles, regulating their disassembly through virion swelling (40, 44–46).…”