Structural insights into coronavirus entry.

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Coronaviruses (CoVs) have caused outbreaks of deadly pneumonia in humans since the beginning of the 21st century. The severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2002 and was responsible for an epidemic that spread to five continents with a fatality rate of 10% before being contained in 2003 (with additional cases reported in 2004). The Middle-East respiratory syndrome coronavirus (MERS-CoV) emerged in the Arabian Peninsula in 2012 and has caused recurrent outbreaks in humans with a fatality rate of 35%. SARS-CoV and MERS-CoV are zoonotic viruses that crossed the species barrier using bats/palm civets and dromedary camels, respectively. No specific treatments or vaccines have been approved against any of the six human coronaviruses, highlighting the need to investigate the principles governing viral entry and cross-species transmission as well as to prepare for zoonotic outbreaks which are likely to occur due to the large reservoir of CoVs found in mammals and birds. Here, we review our understanding of the infection mechanism used by coronaviruses derived from recent structural and biochemical studies.

Keywords: Coronavirus, Spike glycoprotein, Fusion protein, Membrane fusion, Proteolytic activation, Vaccine design


three dimensional
angiotensin-converting enzyme 2
amino-peptidase N
cryo-electron microscopy
dipeptidyl peptidase 4
antigen-binding fragment of an antibody
Middle-East respiratory syndrome coronavirus
mouse hepatitis virus
porcine δ-CoV
porcine epidemic diarrhea virus
severe acute respiratory syndrome coronavirus
transmissible gastroenteritis virus

1. Introduction

Coronaviruses (CoVs) are enveloped viruses with a positive sense RNA genome, that belong to the subfamily Coronavirinae within the family Coronaviridae, which is part of the Nidovirales order. They are classified in four genera (α, β, γ, and δ) and four lineages are recognized whithin the β-CoV genus (A, B, C and D). CoVs cause a variety of respiratory and enteric diseases in mammalian and avian species. Until recently, CoVs were considered to be pathogens with a largely veterinary relevance but with limited impact on human health. However, outbreaks of severe acute respiratory syndrome (SARS) in 2002–2004 and of Middle-East respiratory syndrome (MERS) starting in 2012, with fatality rates of 10% and 35%, respectively, led CoVs to be recognized as zoonotic threats with pandemic potential. Four other CoVs are endemic in the human population and cause up to 30% of mild respiratory tract infections as well as occasional severe disease in young children, the elderly or immunocompromised individuals (Isaacs et al., 1983; Su et al., 2016). These viruses are HCoV-NL63 and HCoV-229E (α-CoVs) as well as HCoV-OC43 and HCoV-HKU1 (β-CoVs). Numerous SARS-CoV and MERS-CoV-like viruses currently circulate in bats and dromedaries making outbreaks of highly pathogenic human CoVs a global health threat (Ge et al., 2013; Haagmans et al., 2014; Hu et al., 2017; Menachery et al., 2015, Menachery et al., 2016; Sabir et al., 2016).

The CoV virion contains at least four structural proteins: spike (S), envelope (E), membrane (M) and nucleocapsid (N). In contrast to other β-CoV lineages, lineage A CoVs also encode a hemagglutinin–esterase which serves as receptor-destroying enzyme to facilitate release of viral progeny from infected cells and escape from attachment to non-permissive host cells or decoys (Bakkers et al., 2017, Bakkers et al., 2016). S is a class 1 viral fusion protein that promotes host attachment and fusion of the viral and cellular membranes during entry (Bosch et al., 2003). As a consequence, S determines host range and cell tropism. S is also the main target of neutralizing antibodies elicited during infection and the focus of vaccine design. S is trimeric and each protomer is synthesized as a single polypeptide chain of 1100–1600 residues, depending on the CoV species. For many CoVs, S is processed by host proteases to generate two functional subunits, designated S1 and S2, which remain non-covalently bound in the prefusion conformation (Bosch et al., 2003). The S1 subunit comprises the apex of the S trimer, including the receptor-binding domains, and stabilizes the prefusion state of the S2 fusion machinery, which is anchored in the viral membrane. For all CoVs, S is further cleaved by host proteases at the so-called S2’ site located immediately upstream of the fusion peptide. This cleavage has been proposed to activate the protein for membrane fusion via large-scale, irreversible conformational changes (Heald-Sargent and Gallagher, 2012; Millet and Whittaker, 2015).

Although several class 1 viral fusion proteins have been extensively studied, CoV S proteins have proven reluctant to structural characterization until recently. Structural studies were largely limited to X-ray crystallographic analysis of isolated receptor-binding domains in complex with viral receptor ectodomains or neutralizing antibodies (Li et al., 2005a; Lu et al., 2013; Peng et al., 2011; Prabakaran et al., 2006; Reguera et al., 2012; Wang et al., 2013; Wong et al., 2017; Wu et al., 2009; Yu et al., 2015) and of the S2 postfusion core (Duquerroy et al., 2005; Gao et al., 2013; Supekar et al., 2004; Xu et al., 2004a, Xu et al., 2004b; Zheng et al., 2006) with the exception of two low-resolution electron microscopy reports (Beniac et al., 2006, Beniac et al., 2007). In the past few years, however, technical advances in single-particle cryo-electron microscopy (cryoEM) (Bai et al., 2013; Brilot et al., 2012; Campbell et al., 2012, Campbell et al., 2015; Li et al., 2013; Punjani et al., 2017; Scheres, 2012) together with the implementation of strategies for the stabilization of CoV S proteins in prefusion conformation (Pallesen et al., 2017; Walls et al., 2017a) led to a surge of structural data for multiple S ectodomain trimers. We review here our current understanding of the mechanism used by CoVs to infect host cells based on recent structural and biochemical studies of S glycoprotein ectodomains in prefusion and postfusion states as well as complexes with known receptors or neutralizing antibodies.

2. Prefusion S architecture

CryoEM studies of the S glycoproteins of mouse hepatitis virus (MHV) and HKU1 led to the first structures at high-enough resolution to obtain an atomic model of the prefusion state (Kirchdoerfer et al., 2016; Walls et al., 2016a). These structures revealed that prefusion S ectodomains are ~ 160 Å-long trimers with a triangular cross-section (Fig. 1A and B).

Fig. 4

CryoEM structures of the SARS-CoV S glycoprotein in complex with the S230 neutralizing antibody. (A–B), Molecular surface representation of a complex with one open, one partially open, and one closed B domain, PDB: 6NB6 (left) and with three open B domains that do not follow threefold symmetry, PDB: 6NB7 (right). The structures are rendered with different colors for each S protomer (light blue, plum and gold) and the S230 Fab heavy (dark magenta) and light (magenta) chains (only the variable domains are shown).


6. Epitope masking and glycan shielding

A deep knowledge of the organization and chemical composition of carbohydrates obstructing the surface of CoV S glycoproteins is key for understanding accessibility to neutralizing antibodies and for guiding the rational development of subunit vaccines and therapeutics. S glycoproteins feature ~ 20–35 predicted N-linked oligosaccharides per protomer. A cryoEM structure of the HCoV-NL63 S ectodomain allowed to visualize for the first time the extensive N-linked glycans covering the surface of a CoV S trimer (Walls et al., 2016b) (Fig. 5 ). A subsequent study revealed that numerous glycosylation sites are strictly or topologically conserved between PDCoV S and HCoV-NL63 S although the two glycoproteins share only 43% amino acid sequence identity and the two viruses belong to different genera infecting different hosts (Xiong et al., 2018). This observation suggested that all CoVs face similar immune pressure in their respective hosts, and that the areas that are masked by the conserved glycans might be key to the function of S. Based on the information gained from the HCoV-NL63 S structure, in which a glycan participates to masking the receptor-binding loops, it was proposed that the S glycan shield is involved in immune evasion, similarly to the well-characterized HIV-1 envelope trimer (Walls et al., 2016b).

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Fig. 5

Organization of the HCoV-NL63 S glycan shield. Ribbon representation of the S ectodomain trimer with N-linked glycans rendered as dark-blue spheres, PDB: 5SZS.

Comparison of the N-linked oligosaccharides of full-length MERS-CoV S derived from virions produced in African green monkey VeroE6 cells, or of a purified MERS-CoV S ectodomain recombinantly produced in HEK293F cells, revealed an extensive overlap of glycan composition, including the presence of hybrid and complex glycans (Walls et al., 2019). Processed oligosaccharides were also observed decorating S trimers at the surface of authentic SARS-CoV virions (Krokhin et al., 2003; Ritchie et al., 2010). These data indicated that at least a fraction of the MERS-CoV and SARS-CoV virions produced in a cell are exposed to the glycan-processing enzymes residing in the Golgi apparatus during assembly and budding, in contrast with previous models of CoV budding (Ng et al., 2003; Stertz et al., 2007).

A common feature observed in the glycosylation patterns of S glycoproteins is the presence of less densely glycosylated regions surrounding the S1/S2 cleavage site and the conserved fusion peptide, near the S2  cleavage site, probably to allow access to activating host proteases and for membrane fusion to take place (Walls et al., 2016b; Walls et al., 2019) (Fig. 5). These “glycan holes” could be targeted for epitope-focused immunogen design or new therapeutic development against CoV, as supported by the identification of a neutralization epitope within a comparable breach of the HIV-1 envelope glycan shield (McCoy et al., 2016).

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7. Concluding remarks

Recent structural and functional characterization of CoV S glycoproteins provided insights into the mechanism used by these viruses to infect host cells and suggested possible strategies for rational design of vaccines and therapeutics. Introducing stabilizing mutations, which prevent the prefusion to postfusion S transition, led to the elicitation of improved neutralization titers in mice and will be a key tool for the design of subunit vaccines against CoVs (Kirchdoerfer et al., 2018; Pallesen et al., 2017). Furthermore, the exposure of the fusion peptide at the surface of prefusion S trimers (Walls et al., 2016a) and its conservation among CoVs indicate it might be an attractive target for broad inhibition of CoV entry. Major antigenic determinants of MHV and SARS-CoV S overlap with the fusion peptide region (Daniel et al., 1993; Zhang et al., 2004) and binding of neutralizing antibodies to this site could putatively prevent fusogenic conformational changes, as proposed for influenza virus hemagglutinin or HIV envelope (Corti et al., 2011; Kong et al., 2016; Lang et al., 2017). Finally, masking strain-specific antigenic regions via engineering of additional N-linked glycosylation sites, as implemented for the MERS-CoV domain B (Du et al., 2016), bears the promise of focusing the immune response on highly conserved epitopes and eliciting broadly neutralizing antibodies against CoVs.

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We acknowledge support from the National Institute of General Medical Sciences (R01GM120553, D.V.), the National Institute of Allergy and Infectious Diseases (HHSN272201700059C, DV), a Pew Biomedical Scholars Award (D.V.), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (D.V.) and the Pasteur Institute (M.A.T.).

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