Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (689)

NSP5 (33)

ProteinN (29)

ProteinS1 (26)

ComplexRdRp (23)


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SARS-CoV-2 Proteins
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    SARS-CoV-2 binding to ACE2 HGNC triggers pericyte-mediated angiotensin-evoked cerebral capillary constriction

    Authors: Chanawee Hirunpattarasilp; Gregory James; Felipe Freitas; Huma Sethi; Josef T Kittler; Jiandong Huo; Raymond J Owens; David Attwell

    doi:10.1101/2021.04.01.438122 Date: 2021-04-01 Source: bioRxiv

    The SARS-CoV-2 receptor, ACE2 HGNC, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 HGNC converts vasoconstricting angiotensin II HGNC into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 HGNC sequence similar to human ACE2 HGNC, angiotensin II HGNC alone evoked only a small capillary constriction, but evoked a large pericyte-mediated capillary constriction generated by AT1 HGNC receptors in the presence of the SARS-CoV-2 receptor binding domain (RBD). The effect of the RBD was mimicked by blocking ACE2 HGNC. A mutated non-binding RBD did not potentiate constriction. A similar RBD-potentiated capillary constriction occurred in human cortical slices. This constriction reflects an RBD-induced decrease in the conversion of angiotensin II HGNC to angiotensin-(1-7). The clinically-used drug losartan inhibited the RBD-potentiated constriction. Thus AT1 receptor blockers could be protective in SARS-CoV-2 infection MESHD by reducing pericyte-mediated blood flow reductions in the brain, and perhaps the heart and kidney.

    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.

    Analysis of glycosylation and disulfide bonding of wild-type SARS-CoV-2 spike PROTEIN glycoprotein

    Authors: Shijian Zhang; Eden P. Go; Haitao Ding; Saumya Anang; John C. Kappes; Heather Desaire; Joseph G. Sodroski

    doi:10.1101/2021.04.01.438120 Date: 2021-04-01 Source: bioRxiv

    The SARS-CoV-2 coronavirus, the etiologic agent of COVID-19 MESHD, uses its spike ( S) glycoprotein PROTEIN anchored in the viral membrane to enter host cells. The S glycoprotein PROTEIN is the major target for neutralizing antibodies elicited by natural infection and by vaccines. Approximately 35% of the SARS-CoV-2 S glycoprotein PROTEIN consists of carbohydrate, which can influence virus infectivity and susceptibility to antibody inhibition. We found that virus-like particles produced by coexpression of SARS-CoV-2 S MESHD, M, E and N proteins PROTEIN contained spike glycoproteins PROTEIN that were extensively modified by complex carbohydrates. We used a fucose-selective lectin to enrich the Golgi-resident fraction of a wild-type SARS-CoV-2 S glycoprotein PROTEIN trimer, and determined its glycosylation and disulfide bond profile. Compared with soluble or solubilized S glycoproteins PROTEIN modified to prevent proteolytic cleavage and to retain a prefusion conformation, more of the wild-type S glycoprotein PROTEIN N-linked glycans are processed to complex forms. Even Asn 234, a significant percentage of which is decorated by high-mannose glycans on soluble and virion S trimers, is predominantly modified in the Golgi by processed glycans. Three incompletely occupied sites of O-linked glycosylation were detected. Viruses pseudotyped with natural variants of the serine/threonine residues implicated in O-linked glycosylation were generally infectious and exhibited sensitivity to neutralization by soluble ACE2 HGNC and convalescent antisera comparable to that of the wild-type virus. Unlike other natural cysteine variants, a Cys15Phe (C15F) mutant retained partial, but unstable, infectivity. These findings enhance our understanding of the Golgi processing of the native SARS-CoV-2 S glycoprotein PROTEIN carbohydrates and could assist the design of interventions.

    Exploring the role of glycans in the interaction of SARS-CoV-2 RBD MESHD and human receptor ACE2

    Authors: Kien Nguyen; Srirupa Chakraborty; Rachael Mansbach; Bette Korber; S. Gnanakaran

    doi:10.1101/2021.03.30.437783 Date: 2021-03-31 Source: bioRxiv

    COVID-19 MESHD is a highly infectious respiratory disease MESHD caused by the novel coronavirus SARS-CoV-2. It has become a global pandemic and its frequent mutations may pose new challenges for vaccine design. During viral infection, the Spike RBD of SARS-CoV-2 binds the human host cell receptor ACE2 HGNC, enabling the virus to enter the host cell. Both the Spike and ACE2 HGNC are densely glycosylated, and it is unclear how distinctive glycan types may modulate the interaction of RBD and ACE2 HGNC. Detailed understanding of these determinants is key for the development of novel therapeutic strategies. To this end, we perform extensive all-atom simulations of the (i) RBD- ACE2 HGNC complex without glycans, (ii) RBD- ACE2 HGNC with oligomannose MAN9 HGNC glycans in ACE2 HGNC, and (iii) RBD- ACE2 HGNC with complex FA2 HGNC glycans in ACE2 HGNC. These simulations identify the key residues at the RBD- ACE2 HGNC interface that form contacts with higher probabilities, thus providing a quantitative evaluation that complements recent structural studies. Notably, we find that this RBD- ACE2 HGNC contact signature is not altered by the presence of different glycoforms, suggesting that RBD- ACE2 HGNC interaction is robust. Applying our simulated results, we illustrate how the recently prevalent N501Y mutation may alter specific interactions with host ACE2 HGNC that facilitate the virus-host binding. Furthermore, our simulations reveal how the glycan on Asn90 of ACE2 HGNC can play a distinct role in the binding and unbinding of RBD. Finally, an energetics analysis shows that MAN9 HGNC glycans on ACE2 HGNC decrease RBD- ACE2 HGNC affinity, while FA2 HGNC glycans lead to enhanced binding of the complex. Together, our results provide a more comprehensive picture of the detailed interplay between virus and human receptor, which is much needed for the discovery of effective treatments that aim at modulating the physical-chemical properties of this virus.

    Upregulated miR-200c HGNC may increase the risk of obese MESHD individuals to severe COVID-19 MESHD

    Authors: Jayanthi Bellae Papannarao; Daryl Schwenke; Patrick J Manning; Rajesh Katare

    doi:10.1101/2021.03.29.21254517 Date: 2021-03-31 Source: medRxiv

    Obesity is a risk factor for coronavirus disease 2019 MESHD ( COVID-19 MESHD) infection, the prevalence of obese MESHD individuals admitted with COVID-19 MESHD ranging between 30 and 60%. Herein we determined whether early changes in microRNAs (miRNAs) could be the underlying molecular mechanism increasing the risk of obese MESHD individuals to COVID-19 MESHD infection. Quantitative real-time PCR analysis of plasma samples for circulating miRNAs showed a significant upregulation of miR-200c HGNC and a small increase in miR HGNC-let-7b obese MESHD individuals. This was associated with significant downregulation of angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC). Both the miRNAs are the direct targets of ACE2 HGNC, the specific functional receptor for severe acute respiratory syndrome coronavirus 2 MESHD. Correlation analysis confirmed a significant negative correlation between ACE2 HGNC and both the miRNAs. Recent studies showed that despite being the functional receptor, inhibition/downregulation of ACE2 HGNC did not reduce the severity of COVID-19 MESHD infection. In contrast, increased angiotensin II HGNC following inhibition of ACE2 HGNC may increase the severity of the disease. Taken together, our novel results identify that upregulation of miR-200c HGNC may increase the susceptibility of obese MESHD individuals to COVID-19 MESHD. Considering miRNA are the earliest molecular regulators, circulating miR-200c HGNC could be a potential biomarker in the early identification of those at the risk of severe COVID-19 MESHD.

    A time series forecasting of the proportion of SARS-CoV-2 N501Y lineage in North America

    Authors: Elena Quinonez; Majid Vahed; Abdolrazagh Hashemi Shahraki; Mehdi Mirsaeidi

    doi:10.1101/2021.03.30.21254648 Date: 2021-03-31 Source: medRxiv

    Introduction: The outbreak of pneumonia MESHD known as SARS-COV-2 and newly-emerging South African (B.1.351), the United Kingdom (B.1.1.7) and Brazil (P.1) variants have led to a more infectious virus and potentially more substantial loss of neutralizing activity by natural infection or vaccine-elicited antibodies. Methods: We identified prevalent mutations using the spike receptor-binding domain (S-RBD) of SARS-CoV-2 deposited in the Nextstrain global database and comparing them to the Wuhan-Hu-1/2019 genomic sequence as a reference. Then we calculated the percentages of mutant genomes from the total regional subsample isolates from December 2019 to the end of January 2021. We developed two separate time series forecasting models for the SARS-CoV-2 B.1.1.7 variant. The computational model used the structure of the S-RBD to examine its interactions with the neutralizing antibody, named CV30 (isolated from a patient), and human angiotensin-converting enzyme 2 HGNC ( hACE-2 HGNC), based on a hybrid algorithm of template-based modeling to predict the affinity of S protein PROTEIN to the neutralizing antibodies and hACE-2 receptor. Results: The proportion of the B.1.1.7 strain in North America is growing fast. From these computations, it seems that the S-RBD and hACE-2 HGNC proteins are less favorable for the South African strain (K417N, E484K, and N501Y) as compared to the wild type structure and more favorable for B.1.1.7 and P.1 variants. In the present of crystallized CV30 neutralizing antibodies, docking scores suggest antibodies can be partially neutralize the B.1.1.7 variant, and, less efficiently, the B.1.351 and P.1 variants. Conclusion: The rapid evolution of SARS-CoV-2 has the potential to allow the newly-emerged B.1.351, and P.1 variants to escape from natural or vaccine-induced neutralizing immunity and viral spreading.

    Rapid characterization of spike variants via mammalian cell surface display

    Authors: Kamyab Javanmardi; Chia-Wei Chou; Cynthia Terrace; Ankur Annapareddy; Tamer S Kaoud; Qingqing Guo; Josh Lutgens; Hayley Zorkic; Andrew P Horton; Elizabeth C Gardner; Giaochau Nguyen; Daniel R Boutz; Jule Goike; Will N Voss; Hung-Che Kuo; Kevin N Dalby; Jimmy D Gollihar; Ilya J Finkelstein

    doi:10.1101/2021.03.30.437622 Date: 2021-03-30 Source: bioRxiv

    The SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN is a critical component of subunit vaccines and a target for neutralizing antibodies. Spike is also undergoing immunogenic selection with clinical variants that increase infectivity and partially escape convalescent plasma. Here, we describe spike display, a high-throughput platform to rapidly characterize glycosylated spike ectodomains across multiple coronavirus-family proteins. We assayed ~200 variant SARS-CoV-2 spikes PROTEIN for their expression, ACE2 HGNC binding, and recognition by thirteen neutralizing antibodies (nAbs). An alanine scan of the N-terminal domain ( NTD HGNC) highlights a public class of epitopes in the N3 and N5 loops that are recognized by most of the NTD HGNC-binding nAbs assayed in this study. Some clinical NTD HGNC substitutions abrogate binding to these epitopes but are circulating at low frequencies around the globe. NTD HGNC mutations in variants of concern B.1.1.7 (United Kingdom), B.1.351 (South Africa), B.1.1.248 (Brazil), and B.1.427/B.1.429 (California) impact spike expression and escape most NTD HGNC-targeting nAbs. However, two classes of NTD HGNC nAbs still bind B.1.1.7 spikes and neutralize in pseudoviral assays. B.1.1351 and B.1.1.248 include compensatory mutations that either increase spike expression or increase ACE2 HGNC binding affinity. Finally, B.1.351 and B.1.1.248 completely escape a potent ACE2 HGNC peptide mimic. We anticipate that spike display will be useful for rapid antigen design, deep scanning mutagenesis, and epitope mapping of antibody interactions for SARS-CoV-2 and other emerging viral threats.

    SARS-CoV-2, a threat to marine mammals? A study from Italian seawaters

    Authors: Cinzia Centelleghe; Sandro Mazzariol; Giovanni Di Guardo; Giancarlo Lauriano

    doi:10.1101/2021.03.29.437540 Date: 2021-03-29 Source: bioRxiv

    Zoonotically transmitted coronaviruses were responsible for three disease outbreaks since 2002, with the Severe Acute Respiratory Syndrome Coronavirus-2 MESHD (SARS-CoV-2) causing the dramatic Coronavirus Disease-2019 ( CoViD-19 MESHD) pandemic, which affected public health, economy, and society on a global scale. The impacts of the SARS-CoV-2 pandemic permeate into our environment and wildlife as well; in particular, concern has been raised about the viral occurrence and persistence in aquatic and marine ecosystems. The discharge of untreated wastewaters carrying infectious SARS-CoV-2 into natural water systems that are home of sea mammals may have dramatic consequences on vulnerable species. The efficient transmission of coronaviruses raise questions regarding the contributions of virus receptors interactions. The main receptor of SARS-CoV-2 is Angiotensin Converting Enzyme-2 HGNC ( ACE-2 HGNC), serving as a functional receptor for the viral spike (S) protein PROTEIN. This study was aimed, through the comparative analysis of the ACE-2 HGNC receptor with the human one, at assessing the susceptibility to SARS-CoV-2 of the different species of marine mammals living in Italian waters. We also determined, by means of immunohistochemistry, ACE-2 HGNC receptor localization in the lung tissue from different cetacean species, in order to provide a preliminary characterization of ACE-2 HGNC expression in the marine mammals respiratory tract. Furthermore, in order to evaluate if and how wastewater management in Italy may lead to susceptible marine mammal populations being exposed to the virus, geo-mapping data of wastewater plants, associated to the identification of specific stretches of coast more exposed to extreme weather events, overlapped to marine mammal population data, were carried out. Results showed the SARS-CoV-2 exposure for marine mammals inhabiting Italian coastal waters. Thus, we highlight the potential hazard of reverse zoonotic transmission of SARS-CoV-2 infection MESHD, along with its impact on marine mammals regularly inhabiting the Mediterranean Sea, whilst also stressing the need of appropriate action to prevent further damage to specific vulnerable populations. Significance Statement Growing concern exists that SARS-CoV-2, as already ascertained for its SARS-CoV and MERS-CoV predecessors, originated from an animal reservoir, performing thereafter its spillover into mankind, that was possibly anticipated by viral passage into a secondary animal host. Within the dramatic SARS-CoV-2 pandemic context, hitherto characterized by over 110 million cases and almost 2,500,000 deaths on a global scale, several domestic and wild animal species have been reported as susceptible to natural and/or experimental SARS-CoV-2 infection MESHD. In this respect, while some marine mammal species are deemed as potentially susceptible to SARS-CoV-2 infection MESHD on the basis of the sequence homology of their ACE-2 HGNC viral receptor with the human one, this study addresses such a critical issue also in stranded sea mammal specimens.

    Enrichment of SARS-CoV-2 entry factors and interacting intracellular genes in peripheral immune cells

    Authors: Abhinandan Devaprasad; Aridaman Pandit

    doi:10.1101/2021.03.29.437515 Date: 2021-03-29 Source: bioRxiv

    SARS-CoV-2 uses ACE2 HGNC and TMPRSS2 HGNC to gain entry into the cell. However, recent studies have shown that SARS-CoV-2 may use additional host factors that are required for the viral lifecycle. Here we used publicly available datasets, CoV associated genes and machine learning algorithms to explore the SARS-CoV-2 interaction landscape in different tissues. We find that in general a small fraction of cells expresses ACE2 HGNC in the different tissues including nasal, bronchi and lungs. We show that a small fraction of immune cells (including T-cells, macrophages, dendritic cells) found in tissues also express ACE2 HGNC. We show that healthy circulating immune cells do not express ACE2 HGNC and TMPRSS2 HGNC. However, a small fraction of circulating immune cells (including dendritic cells, monocytes, T-cells) in the PBMC of COVID-19 MESHD patients express ACE2 HGNC and TMPRSS2 HGNC. Additionally, we found that a large spectrum of cells (in circulation and periphery) in both healthy and COVID-19 MESHD positive patients were significantly enriched for SARS-CoV-2 factors. Thus, we propose that further research is needed to explore if SARS-CoV-2 can directly infect peripheral immune cells to better understand the virus' mechanism of action.

    A lipid nanoparticle RBD-hFc mRNA vaccine protects hACE2 HGNC transgenic mice against lethal SARS-CoV-2 infection MESHD

    Authors: Uri Elia; Shahar Rotem; Srinivas Ramishetti; David Gur; Moshe Aftalion; Adi Bercovich-Kinori; Ron Alcalay; Efi Makdasi; Theodor Chitlaru; Ronit Rosenfeld; Tomer Israely; Sharon Melamed; Inbal Abutbul Ionita; Dganit Danino; Dan Peer; Ofer Cohen

    doi:10.1101/2021.03.29.436639 Date: 2021-03-29 Source: bioRxiv

    The current global COVID-19 pandemic MESHD led to an unprecedented effort to develop effective vaccines against SARS-CoV-2. mRNA vaccines were developed very rapidly during the last year, and became the leading immunization platform against the virus, with highly promising phase-3 results and remarkable efficacy data. Since most animal models are not susceptible to SARS CoV-2 infection MESHD, pre-clinical studies are often limited to infection-prone animals such as hamsters and non-human primates. In these animal models, SARS-CoV-2 infection MESHD results in viral replication and a mild disease disease MESHD. Therefore, the protective efficacy of the vaccine in these animals is commonly evaluated by its ability to elicit immunologic responses, diminish viral replication and prevent weight loss MESHD. Our lab recently reported the design of a SARS-CoV-2 human Fc-conjugated receptor-binding domain (RBD-hFc) mRNA vaccine delivered via lipid nanoparticles (LNPs). These experiments demonstrated the development of a robust and specific immunologic response in RBD-hFc mRNA- vaccinated BALB/c mice. In the current study, we evaluated the protective effect of this RBD-hFc mRNA vaccine by employing the K18- hACE2 HGNC mouse model. We report that administration of RBD-hFc mRNA vaccine to K18- hACE2 HGNC mice led to a robust humoral response comprised of both binding and neutralizing antibodies. In accordance with the recorded immunologic immune response, 70% of vaccinated mice were protected against a lethal dose (3000 plaque forming units) of SARS-CoV-2, while all control animals succumbed to infection. To the best of our knowledge, this is the first non-replicating mRNA vaccine study reporting protection of K18- hACE2 HGNC against a lethal SARS-CoV-2 infection MESHD.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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