Structure of the Lassa virus glycan shield provides a model for immunological resistance

Watanabe, Yasunori; Raghwani, Jayna; Allen, Joel D.; Seabright, Gemma E.; Li, Sai; Moser, Felipe; Huiskonen, Juha T.; Strecker, Thomas; Bowden, Thomas A.; Crispin, Max

doi:10.1073/pnas.1803990115

Cited by 106 publications

(144 citation statements)

References 67 publications

(119 reference statements)

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“…Shielding of the receptor binding sites on the SARS-CoV-2 spike by proximal glycosylation sites (N165, N234, N343) can be observed, especially when the receptor binding domain is in the "down" conformation. The shielding of receptor binding sites by glycans is a common feature of viral glycoproteins and has been observed for SARS-CoV S 4,8 , HIV-1 Env 31 , influenza HA 32,33 , and LASV GPC 21 . Given the functional constraints of receptor binding sites and the subsequent low mutation rates of these residues, it is likely that there has been selective pressure to utilize N-linked glycans as a method to camouflage one of the most conserved and potentially vulnerable areas of their respective glycoproteins 34,35 .…”

Section: Fully Glycosylated Model Of the Sars-cov-2 Spikementioning

confidence: 90%

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Site-specific analysis of the SARS-CoV-2 glycan shield

Watanabe

Allen

Wrapp

et al. 2020

Preprint

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180

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The emergence of the betacoronavirus, SARS-CoV-2 that causes COVID-19, represents a significant threat to global human health. Vaccine development is focused on the principal target of the humoral immune response, the spike (S) glycoprotein, that mediates cell entry and membrane fusion. SARS-CoV-2 S gene encodes 22 N-linked glycan sequons per protomer, which likely play a role in immune evasion and occluding immunogenic protein epitopes. Here, using a site-specific mass spectrometric approach, we reveal the glycan structures on a recombinant SARS-CoV-2 S immunogen. This analysis enables mapping of the glycanprocessing states across the trimeric viral spike. We show how SARS-CoV-2 S glycans differ from typical host glycan processing, which may have implications in viral pathobiology and vaccine design.

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Section: Fully Glycosylated Model Of the Sars-cov-2 Spikementioning

confidence: 90%

“…The stage at which processing is impeded is a signature related to the density and presentation of glycans on the viral spike. For example, the more densely glycosylated spikes of HIV-1 Env and Lassa virus GPC give rise to numerous sites dominated by Man9GlcNAc2 [20][21][22]26 .…”

Section: Localized Impairment To Sars-cov-2 S Glycan Maturationmentioning

confidence: 99%

Site-specific analysis of the SARS-CoV-2 glycan shield

Watanabe

Allen

Wrapp

et al. 2020

Preprint

Self Cite

180

181

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“…These extensive post-translational modifications often mask immunogenic protein epitopes from the host humoral immune system by occluding them with host-derived glycans 21,22 . This phenomenon of immune evasion by molecular mimicry and glycan shielding has been observed and well characterised across other viral glycoproteins, such as HIV-1 envelope protein (Env) [23][24][25] , influenza hemagglutinin (HA) [26][27][28] and Lassa virus glycoprotein complex (LASV GPC) [29][30][31] .…”

Section: Mainmentioning

confidence: 92%

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

Watanabe

Berndsen

Raghwani

et al. 2020

Preprint

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Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoVs) are zoonotic pathogens with high fatality rates and pandemic potential.Vaccine development has focussed on the principal target of the neutralizing humoral immune response, the spike (S) glycoprotein, which mediates receptor recognition and membrane fusion. Coronavirus S proteins are extensively glycosylated viral fusion proteins, encoding around 69-87 N-linked glycosylation sites per trimeric spike. Using a multifaceted structural approach, we reveal a specific area of high glycan density on MERS S that results in the formation of under-processed oligomannose-type glycan clusters, which was absent on SARS and HKU1 CoVs. We provide a comparison of the global glycan density of coronavirus spikes with other viral proteins including HIV-1 envelope, Lassa virus glycoprotein complex, and influenza hemagglutinin, where glycosylation plays a known role in shielding immunogenic epitopes. Consistent with the ability of the antibody-mediated immune response to effectively target and neutralize coronaviruses, we demonstrate that the glycans of coronavirus spikes are not able to form an efficacious high-density global shield to thwart the humoral immune response. Overall, our data reveal how differential organisation of viral glycosylation across class I viral fusion proteins influence not only individual glycan compositions but also the immunological pressure across the viral protein surface.

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“…Thus, these sites could also constitute antibody epitopes and be under immune selection. Furthermore, if this region includes an epitope, the acquisition of N-linked glycosylation at helix h10 may mask the protein surface, similar to the "glycan shields" described for Old World Arenaviruses and HIV-1 (66,67). The occurrence of non-essential N-linked glycosylation sites affecting viral infectivity and replication has been previously described in BUNV (68) and RVFV (69).…”

Section: Structural Analysis Of Orov Proteins and Sites Under Selectionmentioning

confidence: 72%

The evolutionary dynamics of Oropouche Virus (OROV) in South America

Gutierrez

Wise

Pullan

et al. 2019

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The Amazon basin is host to numerous arthropod-borne viral pathogens that cause febrile disease in humans. Among these, Oropouche orthobunyavirus (OROV) is a relatively understudied member of the Peribunyavirales that causes periodic outbreaks in human populations in Brazil and other South American countries. Although several studies have described the genetic diversity of the virus, the evolutionary processes that shape the viral genome remain poorly understood. Here we present a comprehensive study of the genomic dynamics of OROV that encompasses phylogenetic analysis, evolutionary rate estimates, inference of natural selective pressures, recombination and reassortment, and structural analysis of OROV variants. Our study includes all available published sequences, as well as a set of new OROV genomes sequences obtained from patients in Ecuador, representing the first set of viral genomes from this country. Our results show that differing evolutionary processes on the three segments that encompass the viral genome lead to variable evolutionary rates and TMRCAs that could be explained by cryptic reassortment. We also present the discovery of previously unobserved putative N-linked glycosylation sites, and codons which evolve under positive selection on the viral surface proteins, and discuss the potential role of these features in the evolution of the virus through a combined phylogenetic and structural approach.

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Structure of the Lassa virus glycan shield provides a model for immunological resistance

Cited by 106 publications

References 67 publications

Site-specific analysis of the SARS-CoV-2 glycan shield

Site-specific analysis of the SARS-CoV-2 glycan shield

Vulnerabilities in coronavirus glycan shields despite extensive glycosylation

The evolutionary dynamics of Oropouche Virus (OROV) in South America

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