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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (2072)

ProteinN (185)

NSP5 (63)

ProteinS1 (55)

ComplexRdRp (52)


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SARS-CoV-2 Proteins
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    Detection of cross-reactive IgA in saliva against SARS-CoV-2 Spike1 subunit

    Authors: Keiichi Tsukinoki; Tatsuo Yamamoto; Keisuke Handa; Mariko Iwamiya; Satoshi Ino; Takashi Sakurai

    doi:10.1101/2021.03.29.21253174 Date: 2021-04-01 Source: medRxiv

    Abundant secretory IgA (sIgA) in mucus, breast milk MESHD, and saliva provides immunity that prevents infection of mucosal surfaces. sIgA in pre-pandemic breast milk samples have been reported to cross-react with SARS-CoV-2, but whether it also occurs in saliva and, if so, whether it cross-reacts with SARS-CoV-2, has remained unknown. We aimed to clarify whether sIgA in saliva cross-reacts with SARS-CoV-2 spike PROTEIN 1 subunit in individuals who have not been infected MESHD with this virus. The study included 137 (male, n = 101; female, n = 36; mean age, 38.7 [from 24 to 65] years) of dentists and doctors in the Kanagawa Dental University Hospital. Saliva and blood samples were analyzed by PCR and immunochromatography for IgG and IgM, respectively. We then identified patients with saliva samples that were confirmed as PCR- and IgM-negative for COVID-19 MESHD. Proportions of SARS-CoV-2 cross-reactive IgA-positive individuals were determined by enzyme-linked immunosorbent assay using a biotin-labeled spike S1-mFc recombinant protein covering the receptor-binding domain of SARS-CoV-2. The proportion of SARS-CoV-2 cross-reactive IgA-positive individuals was 46.7%, and this correlated negatively with age (r = -0.218, p = 0.01). The proportion of IgA-positive individuals [≥] 50 y was significantly lower than that of patients aged [≤] 49 y (p = 0.005). sIgA was purified from the saliva of all patients, and the salivary sIgA was found to suppress the binding of SARS-CoV-2 spike PROTEIN protein to the ACE-2 receptor. We found SARS-CoV-2 cross-reactive sIgA in the saliva of some participants who had never been infected with the virus, suggesting that sIgA helps prevent SARS-CoV-2 infection MESHD

    SARS-CoV-2 immune evasion by variant B.1.427/B.1.429

    Authors: Matthew McCallum; Jessica Bassi; Anna De Marco; Alex Chen; Alexandra C Walls; Julia Di Iulio; M. Alejandra Tortorici; Mary-Jane Navarro; Chiara Silacci-Fregni; Christian Saliba; Maria Agostini; Dora Pinto; Katja Culap; Siro Bianchi; Stefano Jaconi; Elisabetta Cameroni; John E Bowen; Sasha W Tiles; Matteo Samuele Pizzuto; Sonja Bernasconi Guastalla; Giovanni Bona; Alessandra Franzetti Pellanda; Christian Garzoni; Wesley C Van Voorhis; Laura E Rosen; Gyorgy C Snell; Amalio Telenti; Herbert W Virgin; Luca Piccoli; Davide Corti; David Veesler

    doi:10.1101/2021.03.31.437925 Date: 2021-04-01 Source: bioRxiv

    SARS-CoV-2 entry is mediated by the spike ( S) glycoprotein PROTEIN which contains the receptor-binding domain (RBD) and the N-terminal domain ( NTD HGNC) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California MESHD and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection MESHD or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein PROTEIN. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD HGNC antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD HGNC impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.

    Hydrogel-based slow release of a receptor-binding domain subunit vaccine elicits neutralizing antibody responses against SARS-CoV-2

    Authors: Emily C. Gale; Abigail E. Powell; Gillie A. Roth; Ben S. Ou; Emily L. Meany; Abigail K. Grosskopf; Julia Adamska; Vittoria C. T. M. Picece; Bali Pulendran; Peter S. Kim; Eric Appel

    doi:10.1101/2021.03.31.437792 Date: 2021-04-01 Source: bioRxiv

    The development of an effective vaccine that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19 MESHD. The receptor-binding domain (RBD) of the SARS-CoV-2 spike PROTEIN protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is easy to manufacture and highly stable. Moreover, RBD is a target for neutralizing antibodies and robust cytotoxic T lymphocyte responses. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, most common adjuvant combinations have not been sufficient to improve RBD immunogenicity and none have afforded neutralizing responses in a single-dose RBD vaccine. Here we show that sustained delivery of an RBD subunit vaccine in an injectable hydrogel depot formulation increases total anti-RBD IgG titers compared to bolus administration of the same vaccines. Notably, a SARS-CoV-2 spike PROTEIN-pseudotyped lentivirus neutralization assay revealed neutralizing antibodies in all mice after a single hydrogel vaccine administration comprising clinically-approved adjuvants Alum and CpG. Together, these results suggest that extending the exposure to RBD subunit vaccines significantly enhances the immunogenicity of RBD and induces neutralizing humoral immunity following a single immunization.

    Ultrapotent bispecific antibodies neutralize emerging SARS-CoV-2 variants

    Authors: Hyeseon Cho; Kristina Kay Gonzales-Wartz; Deli Huang; Meng Yuan; Mary Peterson; Janie Liang; Nathan Beutler; Jonathan L. Torres; Yu Cong; Elena Postnikova; Sandhya Bangaru; Chloe Adrienna Talana; Wei Shi; Eun Sung Yang; Yi Zhang; Kwanyee Leung; Lingshu Wang; Linghang Peng; Jeff Skinner; Shanping Li; Nicholas C. Wu; Hejun Liu; Cherrelle Dacon; Thomas Moyer; Melanie Cohen; Ming Zhao; F. Eun-Hyung Lee; Rona S Weinberg; Iyadh Douagi; Robin Gross; Connie Schmaljohn; Amarendra Pegu; John R. Mascola; Michael Holbrook; David Nemazee; Thomas F. Rogers; Andrew B. Ward; Ian A. Wilson; Peter D. Crompton; Joshua Tan

    doi:10.1101/2021.04.01.437942 Date: 2021-04-01 Source: bioRxiv

    The emergence of SARS-CoV-2 variants that threaten the efficacy of existing vaccines and therapeutic antibodies underscores the urgent need for new antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein PROTEIN. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells of COVID-19 MESHD patients. The three most potent antibodies targeted distinct regions of the RBD, and all three neutralized the SARS-CoV-2 variants B.1.1.7 and B.1.351. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD MESHD, competes with the ACE2 receptor, and has limited contact with key variant residues K417, E484 and N501. We designed bispecific antibodies by combining non-overlapping specificities and identified five ultrapotent bispecific antibodies that inhibit authentic SARS-CoV-2 infection MESHD at concentrations of <1 ng/mL. Through a novel mode of action three bispecific antibodies cross-linked adjacent spike proteins PROTEIN using dual NTD/RBD specificities. One bispecific antibody was >100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a 2.5 mg/kg dose. Notably, six of nine bispecific antibodies neutralized B.1.1.7, B.1.351 and the wild-type virus with comparable potency, despite partial or complete loss of activity of at least one parent monoclonal antibody against B.1.351. Furthermore, a bispecific antibody that neutralized B.1.351 protected against SARS-CoV-2 expressing the crucial E484K mutation in the hamster model. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.

    Fine-tuning the Spike: Role of the nature and topology of the glycan shield structure and dynamics of SARS-CoV-2 S MESHD

    Authors: Aoife M Harbison; Carl A Fogarty; Toan K Phung; Akash Satheesan; Benjamin L. Schulz; Elisa Fadda

    doi:10.1101/2021.04.01.438036 Date: 2021-04-01 Source: bioRxiv

    The SARS-CoV-2 spike PROTEIN (S) is a type I fusion glycoprotein, responsible for initiating the infection leading to COVID19 MESHD. As a feature unique of SARS-CoV-2, the thick glycan shield covering the S protein PROTEIN is not only essential for hiding the virus from immune detection, but it also plays multiple functional roles, stabilising the S prefusion open conformation, which is competent for binding the ACE2 primary receptor, and gating the open-to-close transitions. This newly discovered functions of the glycan shield suggest the evolution of its sites of glycosylation is potentially intertwined with the evolution of the overall protein sequence to affect optimal activity. Furthermore, recent studies indicate that the occupancy and structures of SARS-CoV-2 S glycosylation depends MESHD not only on the host-cell, but also on the structural stability of the prefusion trimer; a point that raises important questions about the relative binding competence of different glycoforms. In this work we use multi-microsecond molecular dynamics simulations to characterize the structure and dynamics of different SARS-CoV-2 S MESHD models with different N-glycans at key functional sites, namely N234, N165 and N343. We also assessed the effect of a change in the SARS-CoV-2 S glycan shield topology at N370, due to the recently acquired T372A mutation. Our results indicate that the structures of the N-glycans at N234, N165 and N343 affect the stability of the active (or open) S conformation, and thus its exposure and accessibility. Furthermore, while glycosylation at N370 stabilizes the open S conformation, we find that the N370 glycan binds the closed receptor binding domain (RBD) surface, essentially tying the closed protomers together. These results suggest that the loss of the N370 glycosylation site in SARS-CoV-2 may have increased the availability of the open S form, perhaps contributing to its higher infectivity relative to CoV1 and other variants carrying the sequon. Finally, we discuss these specific changes to the topology of the SARS-CoV-2 S glycan shield through ancestral sequence reconstruction of select SARS strains and discuss how they may have evolved to affect S activity.

    Short-term antibody response and tolerability of one dose of BNT162b2 vaccine in patients receiving hemodialysis

    Authors: Remi Goupil; Mehdi Benlarbi; William Beaubien-Souligny; Annie-Claire Nadeau-Fredette; Chatterjee Debashree; Guillaume Goyette; Caroline Lamarche; Andrés Finzi; Rita S Suri

    doi:10.1101/2021.03.30.21254652 Date: 2021-04-01 Source: medRxiv

    Background: Patients with end-stage kidney disease MESHD receiving in-center hemodialysis are at high risk of exposed to, and dying from, SARS-CoV-2. As impairments in both humoral and cellular immunity are common in this population, their response to vaccination against SARS-CoV-2 is uncertain. Methods: We have followed in-center hemodialysis patients in the Reseau Renal Quebecois MESHD since March 2020 with serial PCRs for COVID-19 MESHD and clinical outcomes. Plasma samples were taken from 58 patients from one center before, and 4 weeks after, vaccination with one dose of the BNT162b2 mRNA vaccine. Anti-RBD (region binding domain of the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN protein) IgG levels were measured using ELISA and compared to levels in 32 health care worker (HCW) controls, as well as levels in convalescent plasma taken from 12 hemodialysis patients 4-12 weeks after COVID-19 MESHD infection. Patients were stratified based on evidence of previous infection with COVID-19 MESHD (positive PCR or antiRBD detectable at baseline). Results: Compared with health-care workers, hemodialysis patients without prior COVID-19 MESHD exhibited significantly lower anti-RBD IgG levels 4 weeks after vaccination (p=0.0007). Anti-RBD IgG was non-detectable in 1/16 (6%) of HCWs, and 25/46 (54%) of dialysis patients (p=0.0008). In dialysis patients previously infected with COVID-19 MESHD, mean anti-RBD levels were significantly lower than their HCW controls (p=0.0031), but not signficantly different than those in convalescent plasma of recently infected dialysis patients (p=NS). No patients reported any symptoms 7 days after vaccination on a standardized questionnaire. Conclusion: The BNT162b2 vaccine was well-tolerated in hemodialysis patients, but failed to elicit a humoral immune response in >50% patients by 4 weeks. Whether these patients develop antibodies or T-cell responses after prolonged observation requires further study. Until then, we recommend that rigorous infection MESHD prevention and control measures in the dialysis unit and outside of it be continued to prevent SARS-CoV-2 infection MESHD in this susceptible population.

    The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against novel viral variants

    Authors: Ronit Rosenfeld; Ohad Mazor; Efi Makdasi; Anat Zvi; Ron Alcalay; Tal Noy-Porat; Eldar Peretz; Adva Mechaly; Yinon Levy; Eyal Epstein; Theodor Chitlaru; Nir Paran; Hadas Tamir; Oren Zimhony; Shay Weiss; Michal Mandelboim; Ella Mendelson; Neta Zuckerman; Ital Nemet; Limor Kliker; Shmuel Yitzhaki; Shmuel C Shapira; Tomer Israely

    doi:10.1101/2021.04.01.438035 Date: 2021-04-01 Source: bioRxiv

    A wide range of SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) were reported to date, most of which target the spike glycoprotein PROTEIN and in particular its receptor binding domain (RBD) and N-terminal domain (NTD) of the S1 subunit. The therapeutic implementation of these antibodies has been recently challenged by the emerging SARS-CoV-2 variants, harboring an extensively-mutated spike versions. Consequently, the re-assessment of mAbs, previously reported to neutralize the original early-version of the virus, represents an assignment of high priority. With respect to the evolving mutations in the virus spike RBD, we evaluated the aptitude of four previously selected mAbs, targeting distinct epitopes, to bind RBD versions harboring individual mutations at positions 501, 477, 484, 439, 417 and 453. Mutations of these residues represent the prevailing worldwide distributed modifications of the RBD, previously reported to mediate escape from antibody neutralization. Additionally, the in vitro neutralization efficacies of the four RBD-specific mAbs, as well as two NTD-specific mAbs, were evaluated against two frequent SARS-CoV-2 variants of concern (VOCs): (i) the B.1.1.7 variant, emerged in the UK and (ii) the B.1.351 variant, emerged in South Africa. B.1.351, was previously suggested to escape many therapeutic mAbs, including those authorized for clinical use. The results of the present study, clearly indicate that in spite of mutation accumulation in the spike of the virus, some neutralizing mAbs preserve their potency to combat SARS-CoV-2 emerged variants. In particular, the previously reported highly potent MD65 mAb is shown to retain its ability to bind the prevalent novel viral mutations and to effectively neutralize the B.1.1.7 and B.1.351 variants of high clinical concern.

    Limiting the priming dose of a SARS CoV-2 vaccine improves virus-specific immunity

    Authors: Sarah Sanchez; Nicole Palacio; Tanushree Dangi; Thomas Ciucci; Pablo Penaloza-MacMaster

    doi:10.1101/2021.03.31.437931 Date: 2021-04-01 Source: bioRxiv

    Since late 2019, SARS-CoV-2 has caused a global pandemic that has infected 128 million people worldwide. Although several vaccine candidates have received emergency use authorization (EUA), there are still a limited number of vaccine doses available. To increase the number of vaccinated individuals, there are ongoing discussions about administering partial vaccine doses, but there is still a paucity of data on how vaccine fractionation affects vaccine-elicited immunity. We performed studies in mice to understand how the priming dose of a SARS CoV-2 vaccine affects long-term immunity to SARS CoV-2. We first primed C57BL/6 mice with an adenovirus-based vaccine encoding SARS CoV-2 spike PROTEIN protein (Ad5-SARS-2 spike), similar to that used in the CanSino and Sputnik V vaccines. This prime was administered either at a low dose (LD) of 106 PFU or at a standard dose (SD) of 109 PFU, followed by a SD boost in all mice four weeks later. As expected, the LD MESHD prime induced lower immune responses relative to the SD prime. However, the LD prime elicited immune responses that were qualitatively superior, and upon boosting, mice that were initially primed with a LD exhibited significantly more potent immune responses. Overall, these data demonstrate that limiting the priming dose of a SARS CoV-2 vaccine may confer unexpected benefits. These findings may be useful for improving vaccine availability and for rational vaccine design.

    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.

    A spatial multi-scale fluorescence microscopy toolbox discloses entry checkpoints of SARS-CoV-2 variants in VeroE6 cells

    Authors: Barbara Storti; Paola Quaranta; Cristina Di Primio; Nicola Clementi; Pier Giorgio Spezia; Vittoria Carnicelli; Giulia Lottini; Emanuele Paolini; Giulia Freer; Michele Lai; Mario Costa; Fabio Beltram; Alberto Diaspro; Mauro Pistello; Riccardo Zucchi; Paolo Bianchini; Giovanni Signore; Ranieri Bizzarri

    doi:10.1101/2021.03.31.437907 Date: 2021-03-31 Source: bioRxiv

    We developed a multi-scale microscopy imaging toolbox to address some major issues related to SARS-CoV-2 interactions with host cells. Our approach harnesses both conventional and super-resolution fluorescence microscopy (Airyscan, STORM, and STED) and easily matches the spatial scale of single virus-cell checkpoints. We deployed this toolbox to characterize subtle issues related to the entry phase of SARS-CoV-2 variants in VeroE6 cells. Our results suggest that the variant of concern B.1.1.7, currently on the rise in several countries by a clear transmission advantage, in these cells outcompetes its ancestor B.1 in terms of a much faster kinetics of entry. Given the molecular scenario (entry by the late pathway and similar fraction of pre-cleaved S protein PROTEIN for B.1.1.7 and B.1), the faster entry of B.1.1.7 could be directly related to the N501Y mutation in the S protein PROTEIN, which is known to strengthen the binding of Spike RBD with ACE2. Remarkably, we also observed directly the significant role of clathrin as mediator of late entry endocytosis, which had been previously suggested in analogy with other CoVs and from experiments on pseudotyped virus models. On overall, we believe that our fluroescence microscopy-based approach is valuable for future studies addressing of how SARS-CoV-2 and its variants interact with cells.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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