Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (257)

ProteinN (13)

NSP5 (6)

ComplexRdRp (6)

ProteinS1 (5)


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SARS-CoV-2 Proteins
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    Epitope classification and RBD binding properties of neutralizing antibodies against SARS-CoV-2 variants of concern

    Authors: Ashlesha Deshpande; Bethany D. Harris; Luis Martinez-Sobrido; James J. Kobie; Mark R Walter

    doi:10.1101/2021.04.13.439681 Date: 2021-04-13 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus-2 MESHD (SAR-CoV-2) causes coronavirus disease 2019 MESHD ( COVID19 MESHD) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN ( S) protein PROTEIN binds to cell surface angiotensin converting enzyme type-II ( ACE2 HGNC) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD MESHD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 HGNC interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4 HGNC, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 HGNC binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 HGNC binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 HGNC binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 HGNC binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC MESHD (B.1.427/B.1.429-California), has evolved to enhance ACE2 HGNC binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT MESHD and VoC strains.

    Antibody and T-cell responses to a single dose of the AZD1222/Covishield vaccine in previously SARS-CoV-2 infected MESHD and naive health care workers in Sri HGNC Lanka

    Authors: Chandima Jeewandara; Achala Kamaladasa; Pradeep D Pushpakumara; Deshni Jayathilaka; Inoka Sepali; Saubhagyagya Danasekara; Dinuka Guruge; Thushali Ranasinghe; Shashika Dayaratne; Thilagaraj T Padmanadan; Gayasha Somathilaka; Deshan Madusanka; Shyrar Tanussiya; Tibutius Jayadas; Heshan Kuruppu; Ayesha Wijesinghe; Nimasha Thashmi; Dushantha Milroy; Achini Nandasena; Nilanka Sanjeewani; Ruwan Wijayamuni; Sudath Samaraweera; Lisa Schimanski; Tiong Tan; Tao Dong; Graham Ogg; Alain Townsend; Gathsaurie Neelika Malavige

    doi:10.1101/2021.04.09.21255194 Date: 2021-04-13 Source: medRxiv

    Background: In order to determine the immunogenicity of a single dose of the AZD1222/Covishield vaccine in a real-world situation, we assessed the immunogenicity, in a large cohort of health care workers in Sri HGNC Lanka. Methods: SARS-CoV-2 antibodies was carried out in 607 naive and 26 previously infected health care workers (HCWs) 28 to 32 days following a single dose of the vaccine. Haemagglutination test (HAT) for antibodies to the receptor binding domain (RBD) of the wild type virus, B.1.1.7, B.1.351 and the surrogate neutralization assay (sVNT) was carried out in 69 naive and 26 previously infected individuals. Spike protein PROTEIN (pools S1 and S2) specific T cell responses were measured by ex vivo ELISpot IFNg HGNC; assays in 76 individuals. Results: 92.9% of previously naive HCWs seroconverted to a single dose of the vaccine, irrespective of age and gender; and ACE2 HGNC blocking antibodies were detected in 67/69 (97.1%) previously naive vaccine recipients. Although high levels of antibodies were found to the RBD of the wild type virus, the titres for B.1.1.7 and B.1.351 were lower in previously naive HCWs. Ex vivo T cell responses were observed to S1 in 63.9% HCWs and S2 in 31.9%. The ACE2 HGNC blocking titres measured by the sVNT significantly increased (p<0.0001) from a median of 54.1 to 97.9 % of inhibition, in previously infected HCWs and antibodies to the RBD for the variants B.1.1.7 and B.1.351 also significantly increased. Discussion: a single dose of the AZD1222/Covishield vaccine was shown to be highly immunogenic in previously naive individuals inducing antibody levels greater than following natural infection. In infected individuals, a single dose induced very high levels of ACE2 HGNC blocking antibodies and antibodies to RBDs of SARS-CoV-2 variants of concern.

    A multiplexed high-throughput neutralization assay reveals a lack of activity against multiple variants after SARS-CoV-2 infection MESHD

    Authors: Craig Fenwick; Priscilla Turelli; Celine Pellaton; Alex Farina; Jeremy Campos; Charlene Raclot; Florence Pojer; Valeria Cagno; Giuseppe Pantaleo; Didier Trono

    doi:10.1101/2021.04.08.21255150 Date: 2021-04-13 Source: medRxiv

    The detection of SARS-CoV-2-specific antibodies in the serum of an individual indicates prior infection or vaccination. However, it provides limited insight into the protective nature of this immune response. Neutralizing antibodies recognizing the viral Spike are far more revealing, yet their measurement traditionally requires virus- and cell-based systems that are costly, time-consuming, poorly flexible and potentially biohazardous. Here we present a cell-free quantitative neutralization assay based on the competitive inhibition of trimeric SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD protein binding to the angiotensin converting enzyme 2 HGNC ( ACE2 HGNC) viral receptor. This high-throughput method matches the performance of the gold standard live virus infectious assay, as verified with a panel of 206 seropositive donors with varying degrees of infection severity and virus-specific IgG titers, achieving 96.7% sensitivity and 100% specificity. Furthermore, it allows for the parallel assessment of neutralizing activities against multiple SARS-CoV-2 Spike PROTEIN variants of concern (VOC), which is otherwise unpredictable even in individuals displaying robust neutralizing antibody responses. Profiling serum samples from 59 hospitalized COVID-19 MESHD patients, we found that although most had high activity against the 2019-nCoV Spike and to a lesser extent the B.1.1.7 variant, only 58% could efficiently neutralize a Spike derivative containing mutations present in the B.1.351 variant. In conclusion, we have developed an assay that has proven its clinical relevance in the large-scale evaluation of effective neutralizing antibody responses to VOC after natural infection and that can be applied to the characterization of vaccine-induced antibody responses and of the potency of human monoclonal antibodies.

    Prediction and evolution of the molecular fitness of SARS-CoV-2 variants: Introducing SpikePro

    Authors: Fabrizio Pucci; Marianne Rooman

    doi:10.1101/2021.04.11.439322 Date: 2021-04-12 Source: bioRxiv

    The understanding of the molecular mechanisms driving the fitness of the SARS-CoV-2 MESHD virus and its mutational evolution is still a critical issue. We built a simplified computational model, called SpikePro, to predict the SARS-CoV-2 fitness MESHD from the amino acid sequence and structure of the spike protein PROTEIN. It contains three contributions: the viral transmissibility predicted from the stability of the spike protein PROTEIN, the infectivity computed in terms of the affinity of the spike protein PROTEIN for the ACE2 HGNC receptor, and the ability of the virus to escape from the human immune response based on the binding affinity of the spike protein PROTEIN for a set of neutralizing antibodies. Our model reproduces well the available experimental, epidemiological and clinical data on the impact of variants on the biophysical characteristics of the virus. For example, it is able to identify circulating viral strains that, by increasing their fitness, recently became dominant at the population level. SpikePro is a useful instrument for the genomic surveillance of the SARS-CoV-2 virus, since it predicts in a fast and accurate way the emergence of new viral strains and their dangerousness. It is freely available in the GitHub repository github.com/3BioCompBio/SpikeProSARS-CoV-2.

    Ultrastructural insight into SARS-CoV-2 attachment, entry and budding in human airway epithelium

    Authors: Andreia L Pinto; Ranjit K Rai; Jonathan C Brown; Paul Griffin; James R Edgar; Anand Shah; Aran Singanayagam; Claire Hogg; Wendy S Barclay; Clare E Futter; Thomas Burgoyne

    doi:10.1101/2021.04.10.439279 Date: 2021-04-11 Source: bioRxiv

    Ultrastructural studies of SARS-CoV-2 infected MESHD cells are crucial to better understand the mechanisms of viral entry and budding within host cells. Many studies are limited by the lack of access to appropriate cellular models. As the airway epithelium is the primary site of infection it is essential to study SARS-CoV-2 infection MESHD of these cells. Here, we examined human airway epithelium, grown as highly differentiated air-liquid interface cultures and infected with three different isolates of SARS-CoV-2 including the B.1.1.7 variant (Variant of Concern 202012/01) by transmission electron microscopy and tomography. For all isolates, the virus infected ciliated but not goblet epithelial cells. Two key SARS-CoV-2 entry molecules, ACE2 HGNC and TMPRSS2 HGNC, were found to be localised to the plasma membrane including microvilli but excluded from cilia. Consistent with these observations, extracellular virions were frequently seen associated with microvilli and the apical plasma membrane but rarely with ciliary membranes. Profiles indicative of viral fusion at the apical plasma membrane demonstrate that the plasma membrane is one site of entry where direct fusion releasing the nucleoprotein PROTEIN-encapsidated genome occurs. Intact intracellular virions were found within ciliated cells in compartments with a single membrane bearing S glycoprotein PROTEIN. Profiles strongly suggesting viral budding from the membrane was observed in these compartments and this may explain how virions gain their S glycoprotein PROTEIN containing envelope.

    Atypical N-glycosylation of SARS-CoV-2 impairs MESHD the efficient binding of Spike- RBM HGNC to the human-host receptor hACE2

    Authors: Gustavo Gamez; Juan A Hermoso; Cesar Carrasco-Lopez; Alejandro Gomez Mejia; Carlos Muskus; Sven Hammerschmidt

    doi:10.1101/2021.04.09.439154 Date: 2021-04-10 Source: bioRxiv

    SARS-CoV-2 internalization by human host cells relies on the molecular binding of its spike glycoprotein PROTEIN (SGP) to the angiotensin-converting-enzyme-2 HGNC (hACE2) receptor. It remains unknown whether atypical N-glycosylation of SGP modulates SARS-CoV-2 tropism for infections MESHD. Here, we address this question through an extensive bioinformatics analysis of publicly available structural and genetic data. We identified two atypical sequons (sequences of N-glycosylation: NGV 481-483 and NGV 501-503), strategically located on the receptor-binding motif ( RBM HGNC) of SGP and facing the hACE2 HGNC receptor. Interestingly, the cryo-electron microscopy structure of trimeric SGP in complex with potent-neutralizing antibodies from convalescent patients revealed covalently-linked N-glycans in NGV 481-483 atypical sequons. Furthermore, NGV 501-503 atypical sequon involves the asparagine-501 residue, whose highly-transmissible mutation N501Y is present in circulating variants of major concerns and affects the SGP- hACE2 HGNC binding-interface through the well-known hotspot-353. These findings suggest that atypical SGP post-translational modifications modulate the SGP- hACE2 HGNC binding-affinity affecting consequently SARS-CoV-2 transmission and pathogenesis.

    Exploring zebrafish larvae as a COVID-19 MESHD model: probable SARS-COV-2 replication in the swim bladder

    Authors: Valerio Laghi; Veronica Rezelj; Laurent Boucontet; Pierre Boudinot; Irene Salinas; Georges Lutfalla; Marco Vignuzzi; Jean-Pierre Levraud

    doi:10.1101/2021.04.08.439059 Date: 2021-04-10 Source: bioRxiv

    Animal models are essential to understand COVID-19 MESHD pathophysiology and for pre-clinical assessment of drugs and other therapeutic or prophylactic interventions. We explored the small, cheap and transparent zebrafish larva as a potential host for the SARS-CoV-2 virus. Bath exposure, as well as microinjection in the coelom, pericardium, brain ventricle, bloodstream, or yolk, did not result in detectable SARS-CoV-2 replication in wild-type larvae. However, when the virus was inoculated in the swim bladder, a modest increase in viral RNA was observed after 24 hours, suggesting a successful infection in some animals. The low infectivity of SARS- CoV-2 in zebrafish was not due to the host type I interferon response, as similar results were observed in type I interferon-deficient animals. We could not detect the induction of transcriptional type I interferon or inflammatory cytokine responses following infection. Overexpression of human ACE2 HGNC in a mosaic fashion by plasmid injection in eggs was not sufficient to increase SARS-CoV-2 infectivity MESHD. In conclusion, wild-type zebrafish larvae appear mostly non-permissive to SARS-CoV-2, except in the swim bladder, an aerial organ sharing similarities with lungs.

    Genome-wide CRISPR activation screen identifies novel receptors for SARS-CoV-2 entry MESHD

    Authors: Shiyou Zhu; Ying Liu; Zhuo Zhou; Zhiying Zhang; Xia Xiao; Zhiheng Liu; Ang Chen; Xiaojing Dong; Feng Tian; Shihua Chen; Yiyuan Xu; Chunhui Wang; Qiheng Li; Xuran Niu; Qian Pan; Shuo Du; Junyu Xiao; Jianwei Wang; Wensheng Wei

    doi:10.1101/2021.04.08.438924 Date: 2021-04-09 Source: bioRxiv

    The ongoing pandemic of coronavirus disease 2019 MESHD ( COVID-19 MESHD) caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) has been endangering worldwide public health and economy. SARS-CoV-2 infects MESHD a variety of tissues where the known receptor ACE2 HGNC is low or almost absent, suggesting the existence of alternative pathways for virus entry. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection MESHD. In addition to known host proteins, i.e PROTEIN. ACE2 HGNC, TMPRSS2 HGNC, and NRP1 HGNC, we identified multiple host components, among which LDLRAD3 HGNC, TMEM30A HGNC, and CLEC4G HGNC were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spike's N-terminal domain ( NTD HGNC). Their essential and physiological roles have all been confirmed in either neuron or liver cells. In particular, LDLRAD3 HGNC and CLEC4G HGNC mediate SARS-CoV-2 entry MESHD and infection in a fashion independent of ACE2 HGNC. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of the therapeutic countermeasures against COVID-19 MESHD.

    Membrane lectins enhance SARS-CoV-2 infection MESHD and influence the neutralizing activity of different classes of antibodies

    Authors: Florian A. Lempp; Leah Soriaga; Martin Montiel-Ruiz; Fabio Benigni; Julia Noack; Young-Jun Park; Siro Bianchi; Alexandra C. Walls; John E. Bowen; Jiayi Zhou; Hanna Kaiser; Maria Agostini; Marcel Meury; Exequiel Dellota Jr.; Stefano Jaconi; Elisabetta Cameroni; Herbert W. Virgin; Antonio Lanzavecchia; David Veesler; Lisa Purcell; Amalio Telenti; Davide Corti

    doi:10.1101/2021.04.03.438258 Date: 2021-04-04 Source: bioRxiv

    Investigating the mechanisms of SARS-CoV-2 cellular infection MESHD is key to better understand COVID-19 MESHD immunity and pathogenesis. Infection, which involves both cell attachment and membrane fusion, relies on the ACE2 HGNC receptor that is paradoxically found at low levels in the respiratory tract, suggesting that additional mechanisms facilitating infection may exist. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN HGNC and the sialic acid-binding Ig-like lectin 1 HGNC ( SIGLEC1 HGNC) function as auxiliary receptors by enhancing ACE2 HGNC-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the N-terminal domain ( NTD HGNC) or to the conserved proteoglycan site at the base of the Receptor Binding Domain (RBD), while poorly neutralizing infection of ACE2 HGNC over-expressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the Receptor Binding Motif ( RBM HGNC), while potently neutralizing infection of ACE2 HGNC over-expressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN HGNC and trigger fusogenic rearrangement of the spike promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2 HGNC-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.

    Identification of lectin receptors for conserved SARS-CoV-2 glycosylation sites

    Authors: David Hoffmann; Stefan Mereiter; Yoo Jin Oh; Vanessa Monteil; Rong Zhu; Daniel Canena; Lisa Hain; Elisabeth Laurent; Clemens Gruber; Maria Novatchkova; Melita Ticevic; Antoine Chabloz; Gerald Wirnsberger; Astrid Hagelkrueys; Friedrich Altmann; Lukas Mach; Johannes Stadlmann; Chris Oostenbrink; Ali Mirazimi; Peter Hinterdorfer; Josef M Penninger

    doi:10.1101/2021.04.01.438087 Date: 2021-04-01 Source: bioRxiv

    New SARS-CoV-2 variants are continuously emerging with critical implications for therapies or vaccinations. All 22 N-glycan sites of SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN remain highly conserved among the variants B.1.1.7, 501Y.V2 and P.1, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate-binding proteins (lectins) to probe critical sugar residues on the full-length trimeric Spike and the receptor binding domain (RBD) of SARS-CoV-2. Two lectins, Clec4g HGNC and CD209c, were identified to strongly bind to Spike. Clec4g HGNC and CD209c binding to Spike was dissected and visualized in real time and at single molecule resolution using atomic force microscopy. 3D modelling showed that both lectins can bind to a glycan within the RBD- ACE2 HGNC interface and thus interferes with Spike binding to cell surfaces. Importantly, Clec4g HGNC and CD209c significantly reduced SARS-CoV-2 infection MESHD SARS-CoV-2 infection MESHDs. These data report the first extensive map and 3D structural modelling of lectin-Spike interactions and uncovers candidate receptors involved in Spike binding and SARS-CoV-2 infections MESHD. The capacity of CLEC4G HGNC and mCD209c lectins to block SARS-CoV-2 viral entry holds promise for pan-variant therapeutic interventions.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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