Early Bunyavirus-Host Cell Interactions

Abstract

The Bunyaviridae is the largest family of RNA viruses, with over 350 members worldwide. Several of these viruses cause severe diseases in livestock and humans. With an increasing number and frequency of outbreaks, bunyaviruses represent a growing threat to public health and agricultural productivity globally. Yet, the receptors, cellular factors and endocytic pathways used by these emerging pathogens to infect cells remain largely uncharacterized. The focus of this review is on the early steps of bunyavirus infection, from virus binding to penetration from endosomes. We address current knowledge and advances for members from each genus in the Bunyaviridae family regarding virus receptors, uptake, intracellular trafficking and fusion.

Keywords: RNA virus; bunyavirus; cell entry; endocytosis; hantavirus; tospovirus; virus membrane fusion; virus receptor.

Figure 1

Schematic representation of a bunyavirus particle. The three viral genomic segments are termed according to their size: S (small), M (medium) and L (large). Abbreviations: G_N: glycoprotein G_N; G_C: glycoprotein G_C; N: nucleoprotein; RdRp: RNA-dependent RNA polymerase.

Figure 2

Schematic representation of bunyavirus G_N and G_C precursor glycoprotein sequences of each genus. Light and dark colored boxes indicate the smallest and highest molecular weight (kDa) of each protein in each genus, respectively. Arrow heads indicate the proteolytic cleavage sites within the glycoprotein precursor by host proteases [32,33]. Red arrows show the localization of the fusion peptide for each genus based on the crystal structure obtained from Rift Valley fever virus Gc [34] and on bioinformatics predictions and biochemical analysis of the glycoproteins from the orthobunyavirus La Crosse, the hantavirus Andes, the nairovirus Crimean-Congo hemorrhagic fever and the tospovirus tomato spotted wilt [35,36,37].

Figure 3

Schematic representation of the bunyavirus G_N and G_C glycoprotein arrangement on the surface of viral particles. The symmetries shown here were obtained by cryo-electron tomography and image reconstruction from Bunyamwera virus (Orthobunyavirus, left panel), Tula virus (TULV) and Hantaan virus (HTNV) (Hantavirus, middle panel), as well as Rift Valley fever (RVFV) and Uukuniemi (UUKV) viruses (Phlebovirus, right panel) [39,40,41,42,43,44,45]. Images were adapted from [44].

Figure 4

Bunyavirus endocytosis. Endocytic internalization of bunyaviruses into animal cells occurs via various pinocytic pathways, which involve several cellular factors, such as adaptor and coat proteins. A growing body of evidence however indicates that several bunyaviruses use clathrin-mediated endocytosis. * Akabane, Black Creek Canal, California encephalitis, Inkoo, Jamestown, Keystone, Melao, Serra do Navio, Snowshoe Hare, Seoul, Tahyna and Trivittatus viruses. SFTSV: severe fever with thrombocytopenia syndrome virus; UUKV: Uukuniemi virus; RVFV: Rift Valley fever virus; LACV: La Crosse virus; CCHFV: Crimean-Congo hemorrhagic fever virus; ANDV: Andes virus; SNV: Sin Nombre virus; HTNV: Hantaan virus; OROV: Oropouche virus.

Figure 5

Bunyavirus intracellular trafficking. This figure shows an overview of the different potential locations of bunyavirus penetration. On the top, the scales indicate the time required by a cargo to traffic from the plasma membrane to an organelle (Δt) and the pH inside the endosomes (pH). Abbreviations: EE: early endosome; ILV: intraluminal vesicle; LE: late endosome; LY: lysosome; µtubule: microtubule; MVB: multivesicular body; LAMP: lysosome-associated membrane glycoproteins.