Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinE (148)

ProteinS (41)

ProteinN (33)

ComplexRdRp (18)

ProteinM (17)


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SARS-CoV-2 Proteins
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    Acceptable Performance of the Abbott ID NOW Among Symptomatic Individuals with Confirmed COVID-19 MESHD

    Authors: William Stokes; Byron Berenger; Takshveer Singh; Ifueko Adeghe; Angela Schneider; Danielle Portnoy; Teagan King; Brittney Scott; Kanti Pabbaraju; Sandy Shokoples; Anita Ah-Ting Wong; Kara Gill; LeeAnn Turnbull; Jia Hu; Graham Tipples

    doi:10.1101/2020.12.24.20248786 Date: 2020-12-30 Source: medRxiv

    INTRODUCTION Point of care diagnostic tests for SARS-CoV-2, such as the ID NOW, have great potential to help combat the COVID-19 MESHD COVID-19 MESHD pandemic. The ID NOW is approved by the United States Food and Drug Administration (FDA) for the detection of SARS-CoV-2 in symptomatic individuals within the first 7 days of symptom onset for COVID-19 MESHD if tested within 1 hour of specimen collection. However, clinical data on the performance of the ID NOW is limited, with many studies deviating from the manufacturer instructions and/or having small sample size. METHODS Adults with COVID-19 MESHD in the community or hospital were recruited into the study. Paired throat swabs were collected, with one throat swab transported immediately in an empty sterile tube to the laboratory for ID NOW testing, and the other transported in universal transport media and tested by an in-house SARS-CoV-2 RT-PCR assay targeting the E-gene PROTEIN. Positive percent agreement (PPA) was calculated. RESULTS 133 individuals were included in the study. 129 samples were positive on either the ID NOW and/or RT-PCR. Assuming any positive result on either assay represents a true positive, PPA of the ID NOW compared to RT-PCR with 95% confidence intervals was 89.1% [82.0% - 94.1%] and 91.6% [85.1% - 95.9%], respectively. When analyzing individuals with symptoms within 7 days and who had the ID NOW performed within an hour, ID NOW PPA increased to 98.2%. DISCUSSION In this study, SARS-CoV-2 results from the ID NOW were reliable, especially when testing was adhered to manufacturer recommendations.

    Environmental Dependence of the Structure of the C-terminal Domain of the SARS-CoV-2 Envelope Protein PROTEIN

    Authors: Kundlik Gadhave; Ankur Kumar; Prateek Kumar; Shivani K Kapuganti; Neha Garg; Michele Vendruscolo; Rajanish Giri; Matthew Hall; Min Shen; Munif Haddad; Giordano Pula; Reiner Mailer; Hartmut Schlueter; Florian Langer; Klaus Pueschel; Kosta Panousis; Evi Stavrou; Coen Maas; Thomas Renne; Sachin B Surade; Omodele Ashiru; Lucia Crippa; Richard Cowan; Matthew W Bowler; Jamie I Campbell; Wing-Yiu Jason Lee; Mark D Carr; David Matthews; Paul Pfeffer; Simon E Hufton; Kovilen Sawmynaden; Jane Osbourn; John McCafferty; Aneesh Karatt-Vellatt

    doi:10.1101/2020.12.29.424646 Date: 2020-12-29 Source: bioRxiv

    The SARS-CoV-2 envelope protein (E PROTEIN) is involved in a broad spectrum of functions in the cycle of the virus, including assembly, budding, envelope formation, and pathogenesis. To enable these activities, E is likely to be capable of changing its conformation depending on environmental cues. To investigate this issue, here we characterised the structural properties of the C-terminal domain of E (E-CTD), which has been reported to interact with host cell membranes. We first studied the conformation of the E-CTD in solution, finding characteristic features of a disordered protein. By contrast, in the presence of large unilamellar vesicles and micelles, which mimic cell membranes, the E-CTD was observed to become structured. The E-CTD was also found to display conformational changes with osmolytes. Furthermore, prolonged incubation of the E-CTD under physiological conditions resulted in amyloid-like fibril formation. Taken together, these findings indicate that the E-CTD can change its conformation depending on its environment, ranging from a disordered state, to a membrane-bound folded state, and an amyloid state. Our results thus provide insight into the structural basis of the role of E in the viral infection process MESHD.

    SARS-CoV-2 Envelope (E) Protein PROTEIN Interacts with PDZ-Domain-2 of Host Tight Junction Protein ZO1

    Authors: Ariel Shepley-McTaggart; Cari A Sagum; Isabela Oliva; Elizabeth Rybakovsky; Katie DiGuilio; Jingjing Liang; Mark T Bedford; Joel Cassel; Marius Sudol; James M Mullin; Ronald N Harty; Andreas C. W. Jenke; Jan Postberg

    doi:10.1101/2020.12.22.422708 Date: 2020-12-23 Source: bioRxiv

    Newly emerged SARS-CoV-2 is the cause of an ongoing global pandemic leading to severe respiratory disease MESHD in humans. SARS-CoV-2 targets epithelial cells in the respiratory tract and lungs, which can lead to amplified chloride secretion and increased leak across epithelial barriers, contributing to severe pneumonia MESHD and consolidation of the lungs as seen in many COVID-19 MESHD patients. There is an urgent need for a better understanding of the molecular aspects that contribute to SARS-CoV-2-induced pathogenesis and for the development of approaches to mitigate these damaging pathologies. The multifunctional SARS-CoV-2 Envelope (E) protein PROTEIN contributes to virus assembly/egress, and as a membrane protein, also possesses viroporin channel properties that may contribute to epithelial barrier damage, pathogenesis, and disease severity. The extreme C-terminal (ECT) sequence of E also contains a putative PDZ-domain binding motif (PBM), similar to that identified in the E protein PROTEIN of SARS-CoV-1. Here, we screened an array of GST-PDZ domain fusion proteins using either a biotin-labeled WT MESHD or mutant ECT peptide from the SARS-CoV-2 E protein PROTEIN. Notably, we identified a singular specific interaction between the WT E peptide and the second PDZ domain of human Zona Occludens-1 HGNC ( ZO1 HGNC), one of the key regulators of TJ formation/integrity in all epithelial tissues. We used homogenous time resolve fluorescence (HTRF) as a second complementary approach to further validate this novel modular E- ZO1 HGNC interaction. We postulate that SARS-CoV-2 E interacts with ZO1 HGNC in infected epithelial cells, and this interaction may contribute, in part, to tight junction damage and epithelial barrier compromise in these cell layers leading to enhanced virus spread and severe respiratory dysfunction MESHD that leads to morbidity. Prophylactic/therapeutic intervention targeting this virus-host interaction may effectively reduce airway barrier damage and mitigate virus spread.

    SARS-CoV-2 RNA quantification using droplet digital RT-PCR

    Authors: Natalie N. Kinloch; Winnie Dong; Kyle D Cobarrubias; Hanwei Sudderuddin; Nancy Matic; Julio S.G. Montaner; Victor Leung; Christopher Fong Jen Lowe; Chanson J Brumme; Zabrina L. Brumme

    doi:10.1101/2020.12.21.423898 Date: 2020-12-23 Source: bioRxiv

    Quantitative viral load assays have transformed our understanding of - and ability to manage - viral diseases. They hold similar potential to advance COVID-19 MESHD control and prevention, but SARS-CoV-2 viral load tests are not yet widely available. SARS-CoV-2 molecular diagnostic tests, which typically employ real-time reverse transcriptase-polymerase chain reaction (RT-PCR), yield semi-quantitative results only. Reverse transcriptase droplet digital PCR (RT-ddPCR), a technology that partitions each reaction into 20,000 nanolitre-sized droplets prior to amplification, offers an attractive platform for SARS-CoV-2 RNA quantification. We evaluated eight primer/probe sets originally developed for real-time RT-PCR-based SARS-CoV-2 diagnostic tests for use in RT-ddPCR, and identified three (Charite-Berlin E-Sarbeco and Pasteur Institute IP2 HGNC and IP4) as the most efficient, precise and sensitive for RT-ddPCR-based SARS-CoV-2 RNA quantification. Analytical efficiency of the E-Sarbeco primer/probe set, for example, was ~83%, while assay precision, as measured by the coefficient of variation, was ~2% at 1000 input copies/reaction. Lower limits of quantification and detection for this primer/probe set were 18.6 and 4.4 input SARS-CoV-2 RNA copies/reaction, respectively. SARS-CoV-2 RNA viral loads in a convenience panel of 48 COVID-19 MESHD-positive diagnostic specimens spanned a 6.2log10 range, confirming substantial viral load variation in vivo. We further calibrated RT-ddPCR-derived SARS-CoV-2 E gene PROTEIN copy numbers against cycle threshold (Ct) values from a commercial real-time RT-PCR diagnostic platform. The resulting log-linear relationship can be used to mathematically derive SARS-CoV-2 RNA copy numbers from Ct values, allowing the wealth of available diagnostic test data to be harnessed to address foundational questions in SARS-CoV-2 biology.

    Surface proteins of SARS-CoV-2 drive airway epithelial cells to induce interferon-dependent inflammation MESHD

    Authors: Gautam Anand; Alexandra M Perry; Celeste L Cummings; Emma St. Raymond; Regina A Clemens; Ashley L Steed

    doi:10.1101/2020.12.14.422710 Date: 2020-12-14 Source: bioRxiv

    SARS-CoV-2, the virus that has caused the COVID-19 pandemic MESHD, robustly activates the host immune system in critically ill MESHD patients. Understanding how the virus engages the immune system will facilitate the development of needed therapeutic strategies. Here we demonstrate both in vitro and in vivo that the SARS-CoV-2 surface proteins Spike (S PROTEIN) and Envelope (E) activate the key immune signaling interferon (IFN) pathway in both immune and epithelial cells independent of viral infection MESHD and replication. These proteins induce reactive oxidative species generation and increases in human and murine specific IFN-responsive cytokines and chemokines, similar to their upregulation in critically ill COVID-19 MESHD patients. Induction of IFN signaling is dependent on canonical but discrepant inflammatory signaling mediators as the activation induced by S is dependent on IRF3 HGNC, TBK1 HGNC, and MYD88 HGNC while that of E is largely MYD88 HGNC independent. Furthermore, these viral surface proteins, specifically E, induced peribronchial inflammation MESHD and pulmonary vasculitis MESHD in a mouse model. Finally we show that the organized inflammatory infiltrates are dependent on type I IFN signaling, specifically in lung epithelial cells. These findings underscore the role of SARS-CoV-2 surface proteins, particularly the understudied E protein PROTEIN, in driving cell specific inflammation MESHD and their potential for therapeutic intervention. Author SummarySARS-CoV-2 robustly activates widespread inflammation MESHD, but we do not understand mechanistically how the virus engages the immune system. This knowledge will facilitate the development of critically needed therapeutic strategies to promote beneficial immune responses will dampening harmful inflammation MESHD. Here we demonstrate that SARS-CoV-2 surface proteins spike PROTEIN and envelope alone activated innate cell function and the interferon signaling pathway. This activation occurred in both immune and epithelial cells, and mechanistic studies demonstrated dependence on known key inflammatory signaling mediators, IRF3 HGNC, TBK1 HGNC, and MYD88 HGNC. In animal studies, we showed that these viral surface proteins induce epithelial cell IFN-dependent lung pathology, reminiscent to acute COVID-19 MESHD pulmonary infection MESHD. These findings underscore the need for further investigation into the role of SARS-CoV-2 surface proteins, particularly the understudied E protein PROTEIN, in driving cell specific inflammation MESHD.

    IGI-LuNER: single-well multiplexed RT-qPCR test for SARS-CoV-2

    Authors: Elizabeth C. Stahl; Connor A. Tsuchida; Jennifer R. Hamilton; Enrique Lin-Shiao; Shana L. McDevitt; Erica A. Moehle; Lea B. Witkowsky; C. Kimberly Tsui; Kathleen Pestal; Holly K. Gildea; Matthew McElroy; Amanda Keller; Iman Sylvain; Clara Williams; Ariana Hirsh; Alison Ciling; Alexander J. Ehrenberg; - SARS-CoV-2 consortium; Fyodor D. Urnov; Bradley R. Ringeisen; Petros Giannikopoulos; Jennifer A. Doudna

    doi:10.1101/2020.12.10.20247338 Date: 2020-12-11 Source: medRxiv

    Commonly used RT-qPCR-based SARS-CoV-2 diagnostics require 2-3 separate reactions or rely on detection of a single viral target, adding time and cost or risk of false-negative results. Currently, no test combines detection of widely used SARS-CoV-2 E- and N-gene PROTEIN targets and a sample control in a single, multiplexed reaction. We developed the IGI-LuNER RT-qPCR assay using the Luna Probe Universal One-Step RT-qPCR master mix with publicly available primers and probes to detect SARS-CoV-2 N gene PROTEIN, E gene PROTEIN, and human RNase P (NER). This combined, cost-effective test can be performed in 384-well plates with detection sensitivity suitable for clinical reporting, and will aid in future sample pooling efforts, thus improving throughput of SARS-CoV-2 detection. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/20247338v2_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@74929corg.highwire.dtl.DTLVardef@1457971org.highwire.dtl.DTLVardef@2825ddorg.highwire.dtl.DTLVardef@1cde2b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

    Binding of SARS-CoV-2 spike PROTEIN protein to ACE2 HGNC is disabled by thiol-based drugs; evidence from in vitro SARS-CoV-2 infection MESHD studies.

    Authors: Kritika Khanna; Wilfred Raymond; Annabelle R Charbit; Jing Jin; Irina Gitlin; Monica Tang; Hannah S Sperber; Sergej Franz; Satish Pillai; Graham Simmons; John V Fahy; Suparerk Borwornpinyo; Arunee Thitithanyanont; Suradej Hongeng; Casey Barton Behravesh; Rebecca Fischer; Gabriel L Hamer; Marion Frankenberger; Lorenz Nowak; Katharina Heinig; Ina Koch; Mircea G Stoleriu; Anne Hilgendorff; Juergen Behr; Andreas Pichlmair; Benjamin Schubert; Fabian J Theis; Dirk H Busch; Herbert B Schiller; Kilian Schober; Evangelos J Giamarellos-Bourboulis; Timothy E Sweeney

    doi:10.1101/2020.12.08.415505 Date: 2020-12-08 Source: bioRxiv

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), and the SARS-CoV-2 spike PROTEIN protein is an envelope PROTEIN glycoprotein that binds angiotensin converting enzyme 2 as an entry receptor. The capacity of enveloped viruses to infect host MESHD cells depends on a precise thiol/disulfide balance in their surface glycoprotein complexes. To determine if cystines MESHD in the SARS-CoV-2 spike PROTEIN protein maintain a native binding interface that can be disrupted by drugs that cleave cystines, we tested if thiol-based drugs have efficacy in receptor binding and cell infection assays. We found that thiol-based drugs, cysteamine and WR-1065 (the active metabolite of amifostine) in particular, decrease binding of SARS-CoV-2 spike PROTEIN protein to its receptor, decrease the entry efficiency of SARS-CoV-2 spike PROTEIN pseudotyped virus, and inhibit SARS-CoV-2 live virus infection MESHD. Our findings uncover a vulnerability of SARS-CoV-2 to thiol-based drugs and provide rationale to test thiol-based drugs, especially cysteamine and amifostine, as novel treatments for COVID-19 MESHD. One Sentence SummaryThiol-based drugs decrease binding of SARS-CoV-2 spike PROTEIN protein to its receptor and inhibit SARS-CoV-2 cell entry.

    Galectin antagonist use in mild cases of SARS-CoV-2 cases; pilot feasibility randomised, open label, controlled trial

    Authors: ALBEN SIGAMANI; ALBEN SIGAMANI; MADHAVI KADAMBI; MATHU RUTHRA; SUDHISHMA SHIVAPRASAD; ANUP CHUGANI; HANA CHEN-WALDEN; THOMASKUTTY ALUMPARAMBILL; DAVID PLATT

    doi:10.1101/2020.12.03.20238840 Date: 2020-12-04 Source: medRxiv

    ImportanceNovel SARS-CoV-2 virus has infected nearly half a billion people across the world and is highly contagious. There is a need for a novel mechanism to block viral entry and stop its replication. BackgroundSpike protein N PROTEIN terminal domain (NTD) of the novel SARS-CoV-2 is essential for viral entry and replication in human cell. Thus the S1 NTD of human coronavirus family, which is similar to a galectin binding site - human galactose binding lectins, is a potential novel target for early treatment in COVID-19 MESHD. ObjectivesTo study the feasibility of performing a definitive trial of using galectin antagonist - Prolectin HGNC-M as treatment for mild, symptomatic, rRT-PCR positive, COVID-19 MESHD. Main outcomes and measuresCycle threshold (Ct) value is number of cycles needed to express fluorescence, on real time reverse transcriptase polymerase chain reaction. Ct values expressed for RNA polymerase (Rd/RP) gene +Nucleocapsid gene and the small envelope ( E) genes PROTEIN determine infectivity of the individual. A digital droplet PCR based estimation of the Nucleocapid genes (N1+N2) in absolute copies/L determines active viral replication. Design and interventionPilot Feasibility Randomised Controlled Open-Label, parallel arm, study. Oral tablets of Prolectin HGNC-M were administered along with the best practice, Standard of Care (SoC) and compared against SoC. Voluntarily, consenting individuals, age >18 years, and able to provide frequent nasopharyngeal and oropharyngeal swabs were randomly allocated by REDCap software. The intervention, Prolectin HGNC-M was administered as a multi dose regime of 4 gram tablets. Each tablet contained 2 grams of (1-6)-Alpha-D-mannopyranosil mixed with 2 grams of dietary fibre. Each participant took a single chewable tablet every hour, to a maximum of 10 hours in a day. Tablets were administered only during the daytime, for total of 5 days. ResultsThis pilot trial demonstrated the feasibility to recruit and randomize participants. By day 7, following treatment with Prolectin HGNC-M, Ct value of Rd/Rp + N gene PROTEIN increased by16.41 points, 95% (CI - 0.3527 to 32.48, p=0.047). Similarly, small envelope ( E) gene PROTEIN also increased by 17.75 points (95% CI;-0.1321 to 35.63, p = 0.05). The expression of N1, N2 genes went below detectable thresholds by day 3 (Mann Whitney U = 0.000, p<0.029). rRT-PCR testing done in the clinic on day 1, 7, and 14 had 3 participants (60%) turn negative by day 7 and all turned negative by day 14 and stayed negative until day 28. In the SoC group 2 participants had zero detectable viral loads at baseline, 2 participants tested negative on day 14, and the last participant tested remained positive on day 28. There were no serious adverse events, and all participants were clinically asymptomatic before day 28 with reactive immunoglobulin G (IgG). Trial relevanceThis pilot study proves that it is feasible and safe to perform a trial using a Galectin antagonist in COVID-19 MESHD. This is a novel mechanism for blocking viral entry and its subsequent replication. Trial RegistrationClinical Trials.gov identifier NCT04512027; CTRI ref. CTRI/2020/09/027833

    Amantadin has potential for the treatment of COVID-19 MESHD because it targets known and novel ion channels encoded by SARS-CoV-2

    Authors: Mads Gravers Jeppesen; Trine Lisberg Toft-Bertelsen; Thomas Nitschke Kledal; Mette Marie Rosenkilde

    doi:10.21203/rs.3.rs-121743/v1 Date: 2020-12-04 Source: ResearchSquare

    The dire need for therapies against SARS-CoV-2 infections MESHD is obvious and inspires strategies of repurposing drugs approved for other indications. Current examples are remdesivir (originally developed for ebola treatment) and steroids (anti-inflammatory treatment). Here we propose to use amantadine (an anti-influenza A drug) as a novel, cheap, readily available and effective way to treat COVID-19 MESHD because of its ability to inhibit known ( Protein E PROTEIN) and novel (Orf10) ion channels identified in the virus genome.

    T cell and antibody functional correlates of severe COVID-19 MESHD

    Authors: Krystle K.Q. Yu; Stephanie Fischinger; Malisa T. Smith; Caroline Atyeo; Deniz Cizmeci; Caitlin R. Wolf; Erik D. Layton; Jennifer K. Logue; Melissa S. Aguilar; Kiel Shuey; Carolin Loos; Jingyou Yu; Nicholas Franko; Robert Y. Choi; Anna Wald; Dan H. Barouch; David M. Koelle; Douglas Lauffenburger; Helen Y. Chu; Galit Alter; Chetan Seshadri

    doi:10.1101/2020.11.25.20235150 Date: 2020-11-30 Source: medRxiv

    Comorbid medical illnesses, such as obesity MESHD and diabetes MESHD, are associated with more severe COVID-19 MESHD, hospitalization, and death MESHD. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multi-parameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins PROTEIN in a convalescent cohort of COVID-19 MESHD subjects who were either hospitalized (n=20) or not hospitalized (n=40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4 T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4 T-cells and antibodies targeting the S1 domain of spike among subjects that were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2 which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19 MESHD. Our data suggest that isolated measurements of the magnitudes of spike-specific immune responses are likely insufficient to anticipate vaccine efficacy in high-risk populations.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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