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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

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SARS-CoV-2 Proteins
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    Autoantibodies against Progranulin HGNC and IL-1 receptor antagonist HGNC in critically ill COVID-19 MESHD

    Authors: Lorenz Thurner; Natalie Fadle; Moritz Bewarder; Igor Kos; Evi Regitz; Onur Cetin; Bernhard Thurner; Yvan Fischer; Torben Rixecker; Klaus-Dieter Preuss; Claudia Schormann; Frank Neumann; Sylvia Hartmann; Theresa Bock; Dominic Kaddu-Mulindwa; Birgit Bette; Joerg Thomas Bittenbring; Konstantinos Christofyllakis; Angelika Bick; Vadim Lesan; Zanir Abdi; Sebastian Mang; Andre Becker; Carlos Metz; Frederik Seiler; Johannes Lehmann; Philipp Agne; Thomas Adams; Andreas Link; Christian Werner; Angela Thiel-Bodenstaff; Matthias Reichert; Guy Danziger; Cihan Papan; Jan Pilch; Thorsten Pfuhl; Patrick Wuchter; Christian Herr; Stefan Lohse; Hubert Schrezenmeier; Michael Boehm; Frank Langer; Gereon Gaebelein; Bettina Friesenhahn-Ochs; Robert Bals; Frank Lammert; Sixten Koerper; Juergen Rissland; Christian Lensch; Stephan Stilgenbauer; Soeren L. Becker; Sigrun Smola; Marcin Krawczyk; Philipp Lepper

    doi:10.1101/2021.04.23.441188 Date: 2021-04-26 Source: bioRxiv

    INTRODUCTION: Hyperinflammation is frequently observed in patients with severe COVID-19 MESHD. Inadequate and defective IFN type I responses against SARS-CoV-2, caused by autoantibodies in a proportion of patients, lead to severe courses. In addition, hyperactive responses of the humoral immune system have been described so far. RATIONALE: In the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from patients with severe and critical COVID-19 MESHD was screened by ELISA for antibodies against PGRN HGNC, IL-10 HGNC, IL-18BP HGNC, IL-22BP HGNC and IL-1-RA HGNC. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations. RESULTS: PGRN HGNC-autoantibodies were detected with high titers in 11 of 30 (36.7%), and IL 1 HGNC-RA-autoantibodies in 14 of 30 (46.7%) patients of a discovery cohort with severe to critical COVID-19 MESHD. In a validation cohort of 41 patients with critical COVID-19 MESHD high-titered PGRN HGNC-Abs were detected in 12 (29.3%) and IL-1-RA HGNC-Abs in 19 of 41 patients (46.2%). PGRN HGNC-Abs and IL-1-RA HGNC-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19 MESHD, PGRN HGNC-Abs and IL-1-RA HGNC-Abs were detected significantly less frequently and at low titers. Neither PGRN HGNC- nor IL-1-RA HGNC-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2. PGRN HGNC-Abs were not cross-reactive against SARS-CoV-2 structural proteins or against IL-1-RA HGNC. Plasma levels of both free PGRN HGNC PGRN MESHD and IL-1-RA HGNC were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID controls. Functionally, PGRN HGNC-Abs from patients reduced PGRN HGNC-dependent inhibition of TNF HGNC- signaling in vitro. The pSer81 hyperphosphorylated PGRN HGNC isoform was exclusively detected in patients with high-titer PGRN HGNC-Abs; likewise, a yet unidentified hyperphosphorylated IL-1-RA HGNC isoform was only found in patients with high-titer IL-1-RA HGNC-Abs. No autoantibodies against IL-10 HGNC, IL-18BP HGNC or IL-22BP HGNC were found. CONCLUSION: To conclude, neutralizing autoantibodies to IL-1-RA HGNC and PGRN HGNC occur in a significant proportion of patients with critical COVID-19 MESHD, with a concomitant decrease in circulating PGRN HGNC and IL-1-RA HGNC, which is indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical isoforms of both antigens due to hyperphosphorylation. It remains to be determined whether these secondary modifications are induced by the SARS-CoV-2-infection MESHD itself, or are preexisting and predispose for a critical course.

    Authors: Natalia G Sampaio; Lise Chauveau; Jonny Hertzog; Anne Bridgeman; Gerissa Fowler; Jurgen P Moonen; Maeva Dupont; Rebecca A Russel; Marko Noerenberg; Jan Rehwinkel

    doi:10.1101/2021.03.26.437180 Date: 2021-03-27 Source: bioRxiv

    Human cells respond to infection by SARS-CoV-2, the virus that causes COVID-19 MESHD, by producing cytokines including type I and III interferons (IFNs) and proinflammatory factors such as IL6 HGNC and TNF HGNC. IFNs can limit SARS-CoV-2 replication but cytokine imbalance contributes to severe COVID-19 MESHD. We studied how cells detect SARS-CoV-2 infection MESHD. We report that the cytosolic RNA sensor MDA5 HGNC was required for type I and III IFN induction in the lung cancer MESHD cell line Calu-3 upon SARS-CoV-2 infection MESHD. Type I and III IFN HGNC induction further required MAVS HGNC and IRF3 HGNC. In contrast, induction of IL6 HGNC and TNF HGNC was independent of the MDA5 HGNC- MAVS HGNC- IRF3 HGNC axis in this setting. We further found that SARS-CoV-2 infection MESHD inhibited the ability of cells to respond to IFNs. In sum, we identified MDA5 HGNC as a cellular sensor for SARS-CoV-2 infection MESHD that induced type I MESHD and III IFNs.

    Serological response to COVID-19 MESHD vaccination in IBD MESHD patients receiving biologics

    Authors: Serre-Yu Wong; Rebekah Dixon; Vicky Martinez Pazos; - ICARUS-IBD; Sacha Gnjatic; Jean-Frederic Colombel; Ken Cadwell

    doi:10.1101/2021.03.17.21253848 Date: 2021-03-20 Source: medRxiv

    Objective The impact of medications on COVID-19 MESHD vaccine efficacy in IBD MESHD patients is unknown, as patients with immunosuppressed states and/or treated with immunosuppressants were excluded from vaccine trials. To address this, we evaluated serological responses to COVID-19 MESHD vaccination with the SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN (S) mRNA BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (NIH-Moderna) vaccines in IBD MESHD patients enrolled in an ongoing SARS-CoV-2 sero-survey at the Icahn School of Medicine at Mount Sinai in New York City. Design We obtained sera from 48 patients who had undergone vaccination with one or two vaccine doses. Sera were tested for SARS-CoV-2 anti-RBD total immunoglobulins and IgG (Siemens COV2T and sCOVG assays), anti-Spike IgG (in-house ELISA), and anti-nucleocapsid antibodies (Roche). Results All IBD MESHD patients (15/15) who completed two-dose vaccine schedules achieved seroconversion to high levels. Two IBD MESHD patients with history of COVID-19 MESHD infections and who were seropositive at baseline seroconverted to high levels after the first dose. Concurrent biologic use was 85% (41/48), including 33% of patients (16) on TNF HGNC antagonist monotherapy, 42% (17) on vedolizumab monotherapy, 6% (3) on vedolizumab combination therapy with thiopurine, and 8% (4) ustekinumab; 1 patient was receiving guselkumab for psoriasis MESHD. Three patients (6%) were on oral steroids at the time of vaccination. Conclusion IBD MESHD patients receiving biologics can seroconvert with robust serological responses after complete Pfizer-BioNTech and NIH-Moderna COVID-19 MESHD vaccination. In IBD-patients with previous SARS-CoV-2 seroconversion, a single dose of either vaccine can induce high index values, mirroring findings from the general population.

    Targeting of the NLRP3 HGNC Inflammasome for early COVID-19 MESHD

    Authors: Carlo Marchetti; Kara Mould; Isak W. Tengesdal; William J. Janssen; Charles A. Dinarello

    doi:10.1101/2021.02.24.432734 Date: 2021-02-24 Source: bioRxiv

    Following entry and replication of Severe Acute Respiratory Syndrome-coronavirus MESHD 2 (SARS-CoV-2) into ACE2 expressing cells, the infected cells undergo lysis releasing more virus but also cell contents. In the lung, constitutive cytokines such as IL-1 HGNC are released together with other cell contents. A cascade of inflammatory cytokines ensues, including chemokines and IL-1{beta}, triggering both local as well as systemic inflammation MESHD. This cascade of inflammatory cytokines in patients with COVID-19 MESHD is termed Cytokine Release Syndrome ( CRS MESHD), and is associated with poor outcomes and death MESHD. Many studies reveal that blocking IL-1{beta HGNC} activities in COVID-19 MESHD patients reduces disease severity and deaths MESHD. Here we report highly significant circulating levels of IL-1{beta HGNC}, IL-1 Receptor antagonist HGNC, IL-6 HGNC, TNF HGNC, IL-10 HGNC and soluble urokinase plasminogen activator receptor HGNC in COVID-19 MESHD patients with mild or no symptoms. We also report that in circulating myeloid cells from the same patients, there is increased expression of the NOD-, LRR- and pyrin domain-containing 3 ( NLRP3 HGNC) early in the infection. We observed increased NLRP3 HGNC gene expression in myeloid cells correlated with IL-1{beta HGNC} gene expression and also with elevated circulating IL-1{beta HGNC} levels. We conclude that early in SARS-CoV-2 infection MESHD, NLRP3 HGNC activation takes place and initiates the CRS. Thus, NLRP3 HGNC is a target to reduce the organ damage of inflammatory cytokines of the CRS.

    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.

    A cannabinoid receptor agonist shows anti-inflammatory and survival properties in human SARS-CoV-2-infected iPSC-derived cardiomyocytes MESHD

    Authors: Luiz Guilherme H.S. Aragao; Julia T Oliveira; Jairo R Temerozo; Mayara A Mendes; Jose Alexandre Salerno; Carolina da S. G. Pedrosa; Teresa Puig-Pijuan; Carla Verissimo; Isis M Ornelas; Thayana Torquato; Gabriela Vitoria; Carolina Q. Sacramento; Natalia Fintelman-Rodrigues; Suelen da Silva Gomes Dias; Vinicius Cardoso Soares; Leticia R. Q. Souza; Karina Karmirian; Livia Goto-Silva; Diogo Biagi; Estela M. Cruvinel; Rafael Dariolli; Daniel R. Furtado; Patricia T. Bozza; Helena L. Borges; Thiago Moreno L. Souza; Marilia Zaluar P. Guimaraes; Stevens Rehen

    doi:10.1101/2021.02.20.431855 Date: 2021-02-21 Source: bioRxiv

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), which can infect several organs and lead to loss of vital organ function, especially impacting respiratory capacity. Among the extrapulmonary manifestations of COVID-19 MESHD is myocardial injury MESHD, caused both directly and indirectly by SARS-CoV-2, and which is associated with a high risk of mortality. One of the hallmarks of severe COVID-19 MESHD is the "cytokine storm", at which point the immune system malfunctions, leading to possible organ failure MESHD and death MESHD. Cannabinoids are known to have anti-inflammatory properties by negatively modulating the release of pro-inflammatory cytokines. Herein, we investigated the effects of the cannabinoid agonist WIN 55,212-2 (WIN) on SARS-CoV-2-infected MESHD human iPSC-derived cardiomyocytes (hiPSC-CMs). Although WIN did not modulate angiotensin-converting enzyme II, nor reduced SARS-CoV-2 infection MESHD and replication in hiPSC-CMs at the conditions tested, it had anti-inflammatory and protective effects by reducing the levels of interleukins 6, 8,18 and tumor necrosis factor-alpha HGNC tumor necrosis factor-alpha MESHD ( TNF HGNC-) and lactate dehydrogenase (LDH) activity in these cells without causing hypertrophic cardiac damage MESHD. These findings suggest that cannabinoids should be further investigated as an alternative therapeutic tool for the treatment of COVID-19 MESHD. HighlightsO_LIHuman iPSC-derived cardiomyocytes (hiPSC-CMs) express CB1 HGNC receptor. C_LIO_LIThe cannabinoid receptor agonist, WIN 55,212-2 (WIN), does not influence SARS-CoV-2 infection MESHD in hiPSC-CMs. C_LIO_LIWIN reduces inflammation MESHD and death MESHD in SARS-CoV-2-infected hiPSC-CMs MESHD. C_LI

    Immune characterization and profiles of SARS-CoV-2 infected MESHD patients

    Authors: Martine Policard; Sidharth Jain; Samantha Rego; Sivanesan Dakshanamurthy

    doi:10.1101/2021.02.17.431721 Date: 2021-02-18 Source: bioRxiv

    The spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 MESHD create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S., patients will continue to require pharmacologic intervention to reduce morbidity and mortality as vaccine availability remains limited. The rise of new variants makes the development of therapeutic strategies even more crucial to combat the current pandemic and future outbreaks. Evidence from several studies suggests the host immune response to SARS-CoV-2 infection MESHD plays a critical role in disease pathogenesis. Consequently, host immune factors are becoming more recognized as potential biomarkers and therapeutic targets for COVID-19 MESHD. To develop therapeutic strategies to combat current and future coronavirus outbreaks, understanding how the coronavirus hijacks the host immune system during and after the infection is crucial. In this study, we investigated immunological patterns or characteristics of the host immune response to SARS-CoV-2 infection MESHD that may contribute to the disease severity of COVID-19 MESHD patients. We analyzed large bulk RNASeq and single cell RNAseq data from COVID-19 MESHD patient samples to immunoprofile differentially expressed gene sets and analyzed pathways to identify human host protein targets. We observed an immunological profile of severe COVID-19 MESHD patients characterized by upregulated cytokines, interferon-induced proteins, and pronounced T cell lymphopenia MESHD, supporting findings by previous studies. We identified a number of host immune targets including PERK HGNC, PKR HGNC, TNF HGNC, NF-kB, and other key genes that modulate the significant pathways and genes identified in COVID-19 MESHD patients. Finally, we identified genes modulated by COVID-19 MESHD infection that are implicated in oncogenesis, including E2F7 HGNC and RB1 HGNC, suggesting a mechanism by which cancer MESHD may arise in patients infected with SARS-CoV2. Further clinical investigation of these targets may lead to bonafide therapeutic strategies to treat the current COVID-19 pandemic MESHD and protect against future outbreaks and viral escape variants.

    Exosomes from COVID-19 MESHD patients carry tenascin-C HGNC and fibrinogen-β in triggering inflammatory signals in distant organ cells

    Authors: Subhayan Sur; Mousumi B. Khatun; Robert Steele; Scott Isbell; Ranjit Ray; Ratna B Ray

    doi:10.1101/2021.02.08.430369 Date: 2021-02-09 Source: bioRxiv

    SARS-CoV-2 infection MESHD causes cytokine storm and overshoot immunity in humans; however, it remains to be determined whether genetic material of SARS-CoV-2 and/or virus induced soluble mediators from lung epithelial cells as natural host are carried out by macrophages or other vehicles at distant organs causing tissue damage. We speculated that exosomes as extracellular vesicles are secreted from SARS-CoV-2 infected MESHD cells may transport messages to other cells of distant organs leading to pathogenic consequences. For this, we took an unbiased proteomic approach for analyses of exosomes isolated from plasma of healthy volunteers and SARS-CoV-2 infected MESHD patients. Our results revealed that tenascin-C HGNC ( TNC HGNC) and fibrinogen-{beta} ( FGB HGNC) are highly abundant in exosomes from SARS-CoV-2 infected MESHD patient's plasma as compared to that of healthy normal controls. Since TNC HGNC and FGB HGNC stimulate pro-inflammatory cytokines via NF-kB pathway, we examined the status of TNF-a HGNC, IL-6 HGNC and CCL5 HGNC expression upon exposure of hepatocytes to exosomes from COVID-19 MESHD patients and observed significant increase when compared with that from healthy subjects. Together, our results demonstrated that soluble mediators, like TNC HGNC and FGB HGNC, are transported through plasma exosomes in SARS-CoV-2 infected MESHD patients and trigger pro-inflammatory cytokine expression in cells of distant organs in COVID-19 MESHD patients.

    Exaggerated cytokine production in human peripheral blood mononuclear cells by recombinant SARS-CoV-2 spike PROTEIN glycoprotein S1 and its inhibition by dexamethasone

    Authors: Olumayokun A Olajide; Victoria U Iwuanyanwu; Izabela Lepiarz-Raba; Alaa A Al-Hindawi

    doi:10.1101/2021.02.03.429536 Date: 2021-02-03 Source: bioRxiv

    An understanding of the pathological inflammatory mechanisms involved in SARS CoV-2 virus infection MESHD is necessary in order to discover new molecular pharmacological targets for SARS-CoV-2 spike PROTEIN glycoprotein. In this study, the effects of a recombinant SARS CoV-2 spike PROTEIN glycoprotein S1 was investigated in human peripheral blood mononuclear cells (PBMCs). Stimulation with spike glycoprotein S1 PROTEIN (100 ng/mL) resulted in significant elevation in the production of TNF HGNC, IL-6 HGNC, IL-1{beta HGNC} and IL-8 HGNC. However, pre-treatment with dexamethasone (100 nM) caused a significant reduction in the release of these cytokines. Further experiments revealed that S1 stimulation of PBMCs increased phosphorylation of NF-{kappa}B HGNC p65 HGNC and I{kappa}B, while increasing I{kappa}B degradation. DNA binding of NF-{kappa}B HGNC p65 HGNC was also significantly increased following stimulation with S1. Treatment of PBMCs with dexamethasone (100 nM) or BAY11-7082 (1 M) resulted in inhibition of S1-induced NF-{kappa}B HGNC activation. Activation of p38 HGNC MAPK by S1 was blocked in the presence of dexamethasone and SKF 86002. CRID3, but not dexamethasone pre-treatment produced significant inhibition of S1-induced activation of NLRP3 HGNC/ caspase 1 HGNC. Further experiments revealed that S1-induced increase in the production of TNF HGNC, IL-6 HGNC, IL-1{beta HGNC} and IL-8 HGNC was reduced in the presence of BAY11-7082 and SKF 86002, while CRID3 pre-treatment resulted in the reduction of IL-1{beta HGNC} production. These results suggest that SARS-CoV-2 spike PROTEIN glycoprotein S1 stimulate PBMCs to release pro inflammatory cytokines through mechanisms involving activation of NF-{kappa}B HGNC, p38 MAPK and NLRP3 HGNC inflammasome. It is proposed that clinical benefits of dexamethasone in COVID-19 MESHD is possibly due to its anti-inflammatory activity in reducing SARS-CoV-2 cytokine storm.

    Early immune pathology and persistent dysregulation MESHD characterise severe COVID-19 MESHD

    Authors: Laura Bergamaschi; Federica Mescia; Lorinda Turner; Aimee Hanson; Prasanti Kotagiri; Benjamin J. Dunmore; Helene Ruffieux; Aloka DeSa; Oisin Huhn; Mark R. Wills; Stephen Baker; Rainer Doffinger; Gordon Dougan; Anne Elmer; Ian G Goodfellow; Ravindra K. Gupta; Myra Hosmillo; Kelvin Hunter; Nathalie Kingston; Paul J. Lehner; Nicholas J. Matheson; Jeremy K. Nicholson; Anna M. Petrunkina; Sylvia Richardson; Caroline Saunders; James E.D. Thaventhiran; Erik J.M. Toonen; Michael P. Weekes; - CambridgeInstituteofTherapeuticImmunologyandInfectiousDisease-NationalInstituteofHealthResearch(CITI; Mark Toshner; Christoph Hess; John R. Bradley; Paul A. Lyons; Kenneth G.C. Smith

    doi:10.1101/2021.01.11.20248765 Date: 2021-01-15 Source: medRxiv

    In a study of 207 SARS-CoV2-infected MESHD individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust immune response, without systemic inflammation MESHD, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed adaptive responses and systemic inflammation MESHD already evident at around symptom onset. Such early evidence of inflammation MESHD suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation MESHD replace those driven by TNF HGNC and IL-6 HGNC. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to "long COVID".

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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