Abstract
In order to multiply and cause disease a virus must transport its genome from outside the cell into the cytosol, most commonly achieved through the endocytic network. Endosomes transport virus particles to specific cellular destinations and viruses exploit the changing environment of maturing endocytic vesicles as triggers to mediate genome release. Previously we demonstrated that several bunyaviruses, which comprise the largest family of negative sense RNA viruses, require the activity of cellular potassium (K+) channels to cause productive infection. Specifically, we demonstrated a surprising role for K+ channels during virus endosomal trafficking. In this study, we have used the prototype bunyavirus, Bunyamwera virus (BUNV), as a tool to understand why K+ channels are required for progression of these viruses through the endocytic network. We report three major findings: First, the production of a dual fluorescently labelled bunyavirus to visualize virus trafficking in live cells. Second, we show that BUNV traffics through endosomes containing high [K+] and that these K+ ions influence the infectivity of virions. Third, we show that K+ channel inhibition can alter the distribution of K+ across the endosomal system and arrest virus trafficking in endosomes. These data suggest high endosomal [K+] is a critical cue that is required for virus infection, and is controlled by cellular K+ channels resident within the endosome network. This highlights cellular K+ channels as druggable targets to impede virus entry, infection and disease.
Highlights
The Bunyaviridae family contains over 350 named members that are separated into 5 genera namely Orthobunyavirus, Hantavirus, Nairovirus, Phlebovirus and Tospovirus [1,2]
Viral infection and endosomal K+ channels requirement for exposure to specific K+ ion concentrations, which we demonstrate is regulated by cellular K+ channels
Using the prototypic orthobunyavirus Bunyamwera virus (BUNV), we recently identified a critical role for cellular K+ channels during the BUNV infectious cycle [12]
Summary
The Bunyaviridae family contains over 350 named members that are separated into 5 genera namely Orthobunyavirus, Hantavirus, Nairovirus, Phlebovirus and Tospovirus [1,2]. Bunyaviruses are generally spherical particles with a diameter between 80–140 nm containing spike-like projections of 5–10 nm composed of two transmembrane glycopolypeptides, Gn and Gc. Key stages of the virus lifecycle are shared across bunyavirus family members in mammalian hosts, including virion movement through the endocytic pathway during virus entry [4], and fusion of the virus envelope with endosomes permitting release of RNPs into the cytosol [5,6,7,8]. Key stages of the virus lifecycle are shared across bunyavirus family members in mammalian hosts, including virion movement through the endocytic pathway during virus entry [4], and fusion of the virus envelope with endosomes permitting release of RNPs into the cytosol [5,6,7,8] Bunyaviruses accomplish this by membrane fusion, mediated by Gc, a Type II fusion protein. The receptors, pathways and cellular factors required during bunyavirus endosomal progression remain largely unidentified and poorly characterized
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