Cryo-EM structure of severe fever with thrombocytopenia syndrome virus

Abstract

The severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne human-infecting bunyavirus, which utilizes two envelope glycoproteins, Gn and Gc, to enter host cells. However, the structure and organization of these glycoproteins on virion surface are not yet known. Here we describe the structure of SFTSV determined by single particle reconstruction, which allows mechanistic insights into bunyavirus assembly at near-atomic resolution. The SFTSV Gn and Gc proteins exist as heterodimers and further assemble into pentameric and hexameric peplomers, shielding the Gc fusion loops by both intra- and inter-heterodimer interactions. Individual peplomers are associated mainly through the ectodomains, in which the highly conserved glycans on N914 of Gc play a crucial role. This elaborate assembly stabilizes Gc in the metastable prefusion conformation and creates some cryptic epitopes that are only accessible in the intermediate states during virus entry. These findings provide an important basis for developing vaccines and therapeutic drugs.

Current Progress of Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) Vaccine Development

“…L protein comprises cap-binding domain, endonuclease domain, and RNA-dependent RNA polymerase (RdRp) enzymatic domain for host mRNA 5′ cap-snatching, as well as viral transcription and genomic replication during the viral lifecycle [ 60 ]. Glycoproteins are translated as a single precursor, then cleaved to Gn and Gc by host proteases to form a virion approximately 100 nm in diameter [ 61 , 62 , 63 , 64 ]. N forms hexamers and interacts with viral RNA (vRNA) to make viral ribonucleoprotein (RNP) to protect the vRNA from degradation by filling the internal virion space [ 63 , 64 , 65 ].…”

“…Glycoproteins are translated as a single precursor, then cleaved to Gn and Gc by host proteases to form a virion approximately 100 nm in diameter [ 61 , 62 , 63 , 64 ]. N forms hexamers and interacts with viral RNA (vRNA) to make viral ribonucleoprotein (RNP) to protect the vRNA from degradation by filling the internal virion space [ 63 , 64 , 65 ]. NSs is a major pathogenic protein that sequesters the host protein complex of tumor progression locus 2 (TPL2)/A20-binding inhibitor of NF-κB activation 2 (ABIN2)/p105 into an inclusion body to induce IL-10 secretion and subsequent anti-inflammatory signaling [ 66 , 67 ].…”

“…Gn forms a heterodimer with pre-fusion Gc, and then 12 heterodimers form three different hexon and penton formations. The hexons and pentons ultimately assemble into an icosahedral virion shell comprising 720 Gn-pre-fusion Gc heterodimers [ 63 , 64 ]. During the viral infection, Gn is presumed to attach to the putative host cell receptor C-C motif chemokine receptor 2 (CCR2) to mediate viral entry [ 73 ].…”

“…During the viral infection, Gn is presumed to attach to the putative host cell receptor C-C motif chemokine receptor 2 (CCR2) to mediate viral entry [ 73 ]. Followed by receptor-mediated endocytosis of the virion particle, Gc mediates membrane fusion between the host cell membrane and the viral envelope to release vRNA into the host cell cytoplasm [ 61 , 62 , 63 , 64 ]. In line with the role of glycoproteins in the viral life cycle, recent studies of SFTSV-neutralizing antibodies from convalescent human sera have reported the Gn head region as the neutralization epitope [ 74 , 75 , 76 ].…”

A full-length glycoprotein mRNA vaccine confers complete protection against severe fever with thrombocytopenia syndrome virus, with broad-spectrum protective effects against bandaviruses

“…Using SFTSV as an example to illustrate the life cycle of bandaviruses, the M segment expresses a glycoprotein precursor within the endoplasmic reticulum, which is then cleaved into the Gn and Gc subunits that subsequently form heterodimers and are immediately incorporated into virions as pentons and hexons within the Golgi apparatus ( 18 ). Next, mature virions are transported to the plasma membrane via vesicles, culminating in the release and completion of the viral replication cycle ( 19 ). When SFTSV enters a host cell, Gn initiates an infection by interacting with dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin and C-C motif chemokine receptor 2 to implement binding ( 20 – 22 ), which is accompanied by membrane fusion induced by Gc within acidic endosomes ( 23 ).…”