preVIEW: COVID-19

Corpus overview

Overview

MeSH Disease

Virus Diseases (93)

COVID-19 (77)

Severe Acute Respiratory Syndrome (33)

Coronavirus Infections (13)

Inflammation (6)


HGNC Genes

angiotensin I converting enzyme 2 (37)

transmembrane serine protease 2 (7)

vitronectin (3)

fuzzy planar cell polarity protein (2)

heat shock protein family A (Hsp70) member 5 (2)


SARS-CoV-2 proteins

ProteinS (93)

NSP5 (6)

ORF8 (3)

ComplexRdRp (2)

ProteinN (2)


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    Antidepressant and antipsychotic drugs reduce viral infection MESHD by SARS-CoV-2 and fluoxetine show antiviral activity against the novel variants in vitro

    Authors: Merve Senem Fred; Suvi Kuivanen; Hasan Ugurlu; Plinio Cabrera Casarotto; Lev Levanov; Kalle Saksela; Olli Vapalahti; Eero Castren

    doi:10.1101/2021.03.22.436379 Date: 2021-03-23 Source: bioRxiv

    Background and Purpose: Repurposing of currently available drugs is a valuable strategy to tackle the consequences of COVID-19 MESHD. Recently, several studies have investigated the effect of psychoactive drugs on SARS-CoV-2 in cell culture models as well as in clinical practice. Our aim was to expand these studies and test some of these compounds against newly emerged variants. Experimental Approach: Several antidepressant drugs and antipsychotic drugs with different primary mechanisms of action were tested in ACE2 HGNC/ TMPRSS2 HGNC-expressing human embryonic kidney cells against the infection by SARS-CoV-2 spike PROTEIN protein-dependent pseudoviruses. Some of these compounds were also tested in human lung epithelial cell line, Calu-1, against the first wave (B.1) lineage of SARS-CoV-2 and the variants of concern, B.1.1.7 and B.1.351. Key Results: Several clinically used antidepressants, including fluoxetine, citalopram, reboxetine, imipramine, as well as antipsychotic compounds chlorpromazine, flupenthixol, and pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability. The antiviral action of several of these drugs was verified in Calu-1 cells against the (B.1) lineage of SARS-CoV-2. By contrast, the anticonvulsant carbamazepine, and novel antidepressants ketamine and its derivatives as well as MAO and phosphodiesterase inhibitors phenelzine and rolipram, respectively, showed no activity in the pseudovirus model. Furthermore, fluoxetine remained effective against pseudo viruses with N501Y, K417N, and E484K spike mutations, and the VoC-1 (B.1.1.7) and VoC-2 (B.1.351) variants of SARS-CoV-2. Conclusion and Implications: Our study confirms previous data and extends information on the repurposing of these drugs to counteract SARS-CoV-2 infection MESHD including different variants of concern.

    Mechanism of inhibition of SARS-CoV-2 infection MESHD by the interaction of the spike glycoprotein PROTEIN with heparin

    Authors: Giulia Paiardi; Stefan Richter; Marco Rusnati; Rebecca C Wade

    id:2103.07722v1 Date: 2021-03-13 Source: arXiv

    Heparin is administered intravenously as an anticoagulant to COVID-19 MESHD patients and via aerosol to treat other lung diseases MESHD. It has recently been found to have antiviral activity against SARS-CoV-2 as it hinders attachment of the virus to the host cell by binding to the virus spike glycoprotein PROTEIN. Here, we describe molecular dynamics simulations to investigate how heparin binds to the spike and the mechanism by which it exerts its antiviral activity. The simulations show that heparin polyanionic chains can bind at long, mostly positively charged patches on the spike, preventing the binding of host cell heparan sulphate proteoglycans to the spike. Heparin can mask both the S1/S2 basic motif, thereby inhibiting furin HGNC cleavage and the formation of the prefusion conformation, and the basic residues of the receptor binding domain (RBD), thus acting on the hinge region responsible for the motion of the RBD between inactive closed and active open conformations of the spike. In simulations of the closed spike, heparin binds the RBD and the N-terminal domain of two adjacent spike subunits and hinders the opening. In simulations of the open spike, heparin binds similarly but induces stabilization of the hinge region and a change in RBD motion. Heparin is therefore able to inhibit host cell attachment directly and by two allosteric mechanisms. Furthermore, the simulations provide insights into how heparan sulphate proteoglycans on the host cell can facilitate viral infection MESHD. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.

    Evolutionary and phenotypic characterization of spike mutations in a new SARS-CoV-2 Lineage reveals two Variants of Interest

    Authors: Paula Ruiz-Rodriguez; Clara Frances-Gomez; Álvaro Chiner-Oms; Mariana G. L&oacutepez; Santiago Jim&eacutenez-Serrano; Irving Cancino-Mu&ntildeoz; Paula Ruiz-Hueso; Manuela Torres-Puente; Maria Alma Bracho; Giuseppe D'Auria; Ll&uacutecia Martinez-Priego; Manuel Guerreiro; Marta Montero-Alonso; Maria Dolores Gomez; Jose Luis Pi&ntildeana; - SeqCOVID-SPAIN consortium; Fernando Gonz&aacutelez-Candelas; I&ntildeaki Comas; Alberto Marina; Ron Geller; Mireia Coscolla

    doi:10.1101/2021.03.08.21253075 Date: 2021-03-12 Source: medRxiv

    Molecular epidemiology of SARS-CoV-2 aims to monitor the appearance of new variants with the potential to change the virulence or transmissibility of the virus. During the first year of SARS-CoV-2 evolution, numerous variants with possible public health impact have emerged. We have detected two mutations in the Spike protein PROTEIN at amino acid positions 1163 and 1167 that have appeared independently multiple times in different genetic backgrounds, indicating they may increase viral fitness MESHD. Interestingly, the majority of these sequences appear in transmission clusters, with the genotype encoding mutations at both positions increasing in frequency more than single-site mutants. This genetic outcome that we denote as Lineage B.1.177.637, belongs to clade 20E and includes 12 additional single nucleotide polymorphisms but no deletions with respect to the reference genome (first sequence in Wuhan). B.1.177.637 appeared after the first wave of the epidemic in Spain, and subsequently spread to eight additional countries, increasing in frequency among sequences in public databases. Positions 1163 and 1167 of the Spike protein PROTEIN are situated in the HR2 domain, which is implicated in the fusion of the host and viral membranes. To better understand the effect of these mutations on the virus, we examined whether B.1.177.637 altered infectivity, thermal stability, or antibody sensitivity. Unexpectedly, we observed reduced infectivity of this variant relative to the ancestral 20E variant in vitro while the levels of viral RNA in nasopharyngeal swabs did not vary significantly. In addition, we found the mutations do not impact thermal stability or antibody susceptibility in vaccinated individuals but display a moderate reduction in sensitivity to neutralization by convalescent sera from early stages of the pandemic. Altogether, this lineage could be considered a Variant of Interest (VOI), we denote VOI1163.7. Finally, we detected a sub-cluster of sequences within VOI1163.7 that have acquired two additional changes previously associated with antibody escape and it could be identified as VOI1163.7.V2. Overall, we have detected the spread of a new Spike variant that may be advantageous to the virus and whose continuous transmission poses risks by the acquisition of additional mutations that could affect pre-existing immunity.

    Molecular strategies for antibody binding and escape of SARS-CoV-2 and its mutations

    Authors: Mohamed Hendy; Samuel Kaufman; Mauricio Ponga

    doi:10.1101/2021.03.04.433970 Date: 2021-03-05 Source: bioRxiv

    The COVID19 MESHD pandemic, caused by SARS-CoV-2, has infected more than 100 million people worldwide. Due to the rapid spreading of SARS-CoV-2 and its impact, it is paramount to find effective treatments against it. Human neutralizing antibodies are an effective method to fight viral infection MESHD. However, the recent discovery of new strains that substantially change the S-protein HGNC S-protein PROTEIN sequence has raised concern about vaccines and antibodies' effectiveness. Here, we investigated the binding mechanisms between the S-protein HGNC S-protein PROTEIN and several antibodies. Multiple mutations were included to understand the strategies for antibody escape in new variants. We found that the combination of mutations K417N and E484K produced higher binding energy to ACE2 HGNC than the wild type, suggesting higher efficiency to enter host cells. The mutations' effect depends on the antibody class. While Class I enhances the binding avidity in the presence of N501Y mutation, class II antibodies showed a sharp decline in the binding affinity. Our simulations suggest that Class I antibodies will remain effective against the new strains. In contrast, Class II antibodies will have less affinity to the S-protein HGNC S-protein PROTEIN, potentially affecting these antibodies' efficiency.

    Discovery of a AhR HGNC flavonoid agonist that counter-regulates ACE2 HGNC expression in rodent models of inflammation MESHD and attenuates ACE2 HGNC-SARS-CoV2 interaction in vitro

    Authors:

    doi:10.1101/2021.02.24.432203 Date: 2021-02-24 Source: bioRxiv

    The severe acute respiratory syndrome MESHD (SARS)-CoV-2, a newly emerged coronavirus first identified in 2019, is the pathogenetic agent od Corona Virus Induced Disease MESHD (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE) 2 HGNC receptor in target tissues. ACE2 HGNC expression is induced in response to inflammation MESHD. The colon expression of ACE2 HGNC is upregulated in patients with inflammatory bowel disease MESHD ( IBD MESHD), highlighting a potential risk of intestinal inflammation MESHD in promoting viral entry in the human body. Because mechanisms that regulate ACE2 HGNC expression in the intestine are poorly understood and there is a need of anti-SARS-CoV2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of ACE2 HGNC in intestinal models of inflammation MESHD. The results of these studies demonstrated that pelargonidin, a natural flavonoid bind and activates the Aryl hydrocarbon Receptor HGNC ( AhR HGNC) in vitro and reverses intestinal inflammation MESHD caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent DSS in a AhR HGNC-dependent manner. In these two models, development of colon inflammation MESHD associated with upregulation of ACE2 HGNC mRNA expression. Colon levels of ACE2 HGNC mRNA were directly correlated with TNF HGNC mRNA levels. In contrast to ACE2 HGNC the angiotensin 1-7 receptor MAS was downregulated in the inflamed tissues. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV2 Spike protein PROTEIN. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV2 Spike protein PROTEIN to ACE2 HGNC and reduces the SARS-CoV2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation MESHD and ACE2 HGNC induction in the inflamed colon in a AhR HGNC-dependent manner.

    IMMUNO-COV™ v2.0: Development and Validation of a High-Throughput Clinical Assay for Measuring SARS-CoV-2-Neutralizing Antibody Titers MESHD

    Authors: Rianna Vandergaast; Timothy Carey; Samantha Reiter; Chase Lathrum; Patrycja Lech; Clement Gnanadurai; Michelle Haselton; Jason Buehler; Riya Narjari; Luke Schnebeck; Anne Roesler; Kara Sevola; Lukkana Suksanpaisan; Alice Bexon; Shruthi Naik; Bethany Brunton; Scott C. Weaver; Grace Rafael; Sheryl Tran; Alina Baum; Christos A. Kyratsous; Kah-Whye Peng; Stephen J. Russell

    doi:10.1101/2021.02.16.21251653 Date: 2021-02-19 Source: medRxiv

    Neutralizing antibodies are key determinants of protection from future infection, yet well-validated high-throughput assays for measuring titers of SARS-CoV-2-neutralizing antibodies are not generally available. Here we describe the development and validation of IMMUNO-COV v2.0 a scalable surrogate virus assay, which titrates antibodies that block infection MESHD of Vero-ACE2 cells by a luciferase-encoding vesicular stomatitis MESHD virus displaying SARS-CoV-2 spike PROTEIN glycoproteins (VSV-SARS2-Fluc). Antibody titers, calculated using a standard curve consisting of stepped concentrations of SARS-CoV-2 spike PROTEIN monoclonal antibody, correlated closely (p < 0.0001) with titers obtained from a gold-standard PRNT50% assay performed using a clinical isolate of SARS-CoV-2. IMMUNO-COV v2.0 was comprehensively validated using data acquired from 242 assay runs performed over seven days by five analysts, utilizing two separate virus lots, and 176 blood samples. Assay performance was acceptable for clinical use in human serum and plasma based on parameters including linearity, dynamic range, limit of blank and limit of detection, dilutional linearity and parallelism, precision, clinical agreement, matrix equivalence, clinical specificity and sensitivity, and robustness. Sufficient VSV-SARS2-Fluc virus MESHD reagent has been banked to test 5 million clinical samples. Notably, a significant drop in IMMUNO-COV v2.0 neutralizing antibody titers was observed over a six-month period in people recovered from SARS-CoV-2 infection MESHD. Together, our results demonstrate the feasibility and utility of IMMUNO-COV v2.0 for measuring SARS-CoV-2-neutralizing antibodies in vaccinated individuals and those recovering from natural infections. Such monitoring can be used to better understand what levels of neutralizing antibodies are required for protection from SARS-CoV-2, and what booster dosing schedules are needed to sustain vaccine-induced immunity.

    Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection MESHD

    Authors: Zhuo Zhou; Xinyi Zhang; Xiaobo Lei; Xia Xiao; Tao Jiao; Ruiyi Ma; Xiaojing Dong; Qi Jiang; Wenjing Wang; Yujin Shi; Tian Zheng; Yuting Tan; Zichun Xiang; Lili Ren; Tao Deng; Zhengfan Jiang; Zhixun Dou; Wensheng Wei; Jianwei Wang

    doi:10.21203/rs.3.rs-235742/v1 Date: 2021-02-12 Source: ResearchSquare

    The global coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic is caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection MESHD remain to be determined. Here, we report that SARS-CoV-2 infection MESHD activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection MESHD induces the cellular level of 2'3'-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection MESHD. We further demonstrate that the expression of spike protein PROTEIN from SARS-CoV-2 and ACE2 HGNC from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS HGNC mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection MESHD, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19 MESHD. In addition, these findings extend our knowledge in host defense against viral infection MESHD by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.

    Effect of RBD (Y453F) mutation in spike glycoprotein PROTEIN of SARS-CoV-2 on neutralizing IgG affinity.

    Authors: Takuma Hayashi; Nobuo Yaegashi; Ikuo Konishi

    doi:10.1101/2021.01.28.21250577 Date: 2021-02-01 Source: medRxiv

    Background: Infection with receptor binding domain (RBD) mutant (Y453F) of the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) from farmed minks is known to widely spread among humans. Methods: We investigated the characteristics of SARS-CoV-2 RBD Y453F mutant using three-dimensional structural analysis. We investigated the effect of the RBD Y453F mutant of SARS-CoV-2 on neutralizing antibodies in serum derived from Corona virus Disease MESHD 2019 ( COVID-19 MESHD) positive patients. Results: Our studies suggest that virus variants with RBD Y453F mutation partially escaped detection by four neutralizing monoclonal antibodies and neutralizing antibodies in serum. Conclusions: Consequently, raising a concern that infection of SARS-CoV-2 MESHD mutants that cause serious symptoms in humans may spread globally.

    Validation of a commercially available indirect assay for SARS-CoV-2 neutralising antibodies using a pseudotyped virus assay

    Authors: Matthew J Murray; Megan McIntosh; Claire Atkinson; Tabitha Mahungu; Edward Wright; Wendy Chatterton; Michael Gandy; Matthew B Reeves

    doi:10.21203/rs.3.rs-197836/v3 Date: 2021-02-01 Source: ResearchSquare

    Objectives To assess whether a commercially available CE-IVD, ELISA-based surrogate neutralisation assay (cPass, Genscript) provides a genuine measure of SARS-CoV-2 neutralisation by human sera, and further to establish whether measuring responses against the RBD of S was a diagnostically useful proxy for responses against the whole S protein PROTEIN.Methods Serum samples from 30 patients were assayed for anti-NP responses, for ‘neutralisation’ by the surrogate neutralisation assay and for neutralisation by SARS-CoV-2 S pseudotyped virus assays utilising two target cell lines. Correlation between assays was measured using linear regression.Results The responses observed within the surrogate neutralisation assay demonstrated an extremely strong, highly significant positive correlation with those observed in both pseudotyped virus assays.Conclusions The tested ELISA-based surrogate assay provides an immunologically useful measure of functional immune responses in a much quicker and highly automatable fashion. It also reinforces that detection of anti-RBD neutralising antibodies alone is a powerful measure of the capacity to neutralise viral infection MESHD.

    Modeling mutational effects on biochemical phenotypes using convolutional neural networks: application to SARS-CoV-2

    Authors: Bo Wang; Eric R Gamazon; Sarah R. Leist; Kendra Gully; Joy Feng; Elaine Bunyan; Danielle Porter; Tomas Cihlar; Stephanie Montgomery; Ralph S. Baric; Michel C. Nussenzweig; Timothy P. Sheahan; Matthew K Robinson; Michael J Morin; Pavel A Nikitin; Karen M Ridge; Bria M Coates; Janet M. Lord; Claire J. Steves

    doi:10.1101/2021.01.28.428521 Date: 2021-01-28 Source: bioRxiv

    Biochemical phenotypes are major indexes for protein structure and function characterization. They are determined, at least in part, by the intrinsic physicochemical properties of amino acids and may be reflected in the protein three-dimensional structure. Modeling mutational effects on biochemical phenotypes is a critical step for understanding protein function and disease mechanism as well as enabling drug discovery. Deep Mutational Scanning (DMS) experiments have been performed on SARS-CoV-2's spike receptor binding domain and the human ACE2 HGNC zinc-binding peptidase domain - both central players in viral infection MESHD and evolution and antibody evasion - quantifying how mutations impact binding affinity and protein expression. Here, we modeled biochemical phenotypes from massively parallel assays, using convolutional neural networks trained on protein sequence mutations in the virus and human host. We found that neural networks are significantly predictive of binding affinity, protein expression, and antibody escape, learning complex interactions and higher-order features that are difficult to capture with conventional methods from structural biology. Integrating the intrinsic physicochemical properties of amino acids, including hydrophobicity, solvent-accessible surface area, and long-range non-bonded energy per atom, significantly improved prediction (empirical p<0.01) though there was such a strong dependence on the sequence data alone to yield reasonably good prediction. We observed concordance of the DMS data and our neural network predictions with an independent study on intermolecular interactions from molecular dynamics (multiple 500 ns or 1 s all-atom) simulations of the spike protein PROTEIN- ACE2 HGNC interface, with critical implications for the use of deep learning to dissect molecular mechanisms. The mutation- or genetically- determined component of a biochemical phenotype estimated from the neural networks has improved causal inference properties relative to the original phenotype and can facilitate crucial insights into disease pathophysiology and therapeutic design.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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