Orthobunyaviruses: From Virus Binding to Penetration into Mammalian Host Cells

Abstract

With over 80 members worldwide, Orthobunyavirus is the largest genus in the Peribunyaviridae family. Orthobunyaviruses (OBVs) are arthropod-borne viruses that are structurally simple, with a trisegmented, negative-sense RNA genome and only four structural proteins. OBVs are potential agents of emerging and re-emerging diseases and overall represent a global threat to both public and veterinary health. The focus of this review is on the very first steps of OBV infection in mammalian hosts, from virus binding to penetration and release of the viral genome into the cytosol. Here, we address the most current knowledge and advances regarding OBV receptors, endocytosis, and fusion.

Keywords: Bunyamwera; La Crosse; Oropouche; Schmallenberg; arbovirus; cell entry; emerging virus; endocytosis; fusion; receptor.

Figure 1

OBV genome and the glycoproteins Gn and Gc. (a) Generic representation of an OBV genome. The name of the three viral genomic RNA segments refers to their size, i.e., S (small), M (medium), and L (large). (b) Schematic representation of the OBV M precursor polypeptide. Arrow heads show the sites proteolytically cleaved by host cell proteases. The red arrowhead indicates the location of the fusion peptide based on bioinformatics predictions and biochemical analysis of LACV glycoproteins [35,36,37]. Abbreviation: TM, transmembrane domain.

Figure 2

(a) Schematic representation of an OBV particle. (b) Schematic representation of the tripodal architecture of the glycoprotein spikes o the surface of a BUNV particle as analyzed by cET [43]. Abbreviations: Gn, glycoprotein Gn; Gc, glycoprotein Gc; N, nucleoprotein N; RdRp L, RNA-dependent RNA polymerase L.

Figure 3

OBV entry into mammalian cells. This figure provides an overview of the entry pathways used by some OBVs to infect host cells. On the left, the scales indicate the time for the trafficking of cargo from the surface to an organelle and the related pH inside endosomal vesicles. Abbreviations: AKAV, Akabane virus; Baf A1, bafilomycin A1; BUNV: Bunyamwera virus; CEV, California encephalitis virus; CME, clathrin-mediated endocytosis; CPZ, chloropromazine; DN, dominant negative; DYN, dynasore; EGFP, enhanced green fluorescent protein; GERV, Germiston virus; HEPase, heparinase; HSPG, heparan sulfate proteoglycan; LACV, La Crosse virus; MβC, methyl-β-cyclodextrin; NH₄Cl, ammonium chloride. OROV, Oropouche virus; SBV, Schmallenberg virus; SUC, sucrose; TEA, tetraethylammonium; * Other viruses using the CME pathway, including the CEV and Inkoo, Jamestown canyon, Keystone, Melao, Serra do Navio, snowshoe hare, Tahnya, and Trivittatus viruses.