Corpus overview


MeSH Disease

Human Phenotype


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    Severe Acute Respiratory Syndrome MESHD Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling

    Authors: Pei-Hui Wang; Yi Zheng; Meng-Wei Zhuang; Lulu Han; Jing Zhang; Mei-Ling Nan; Chengjiang Gao

    doi:10.1101/2020.07.26.222026 Date: 2020-07-27 Source: bioRxiv

    The coronavirus disease MESHD 2019 (COVID-19) caused by Severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) has quickly spread worldwide and has infected more than ten million individuals. One of the typical features of COVID-19 is that both type I and III interferon (IFN)-mediated antiviral immunity are suppressed. However, the molecular mechanism by which SARS-CoV-2 evades this antiviral immunity remains elusive. Here, we report that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway of RIG-I/MDA-5-MAVS signaling. The SARS-CoV2 M protein also dampens type I and III IFN induction stimulated by Sendai virus infection MESHD or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1 and prevents the formation of a multi-protein complex containing RIG-I, MAVS, TRAF3, and TBK1, thus impeding IRF3 phosphorylation, nuclear translocation, and activation. Consequently, the ectopic expression of the SARS-CoV2 M protein facilitates the replication of vesicular stomatitis MESHD stomatitis HP virus (VSV). Taken together, the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of the SARS-CoV-2-induced antiviral immune suppression and sheds light on the pathogenic mechanism of COVID-19.

    Novel surrogate virus neutralization test reveals low serum SERO neutralizing anti-SARS-CoV-2-S antibodies SERO levels in mildly affected COVID-19 convalescents

    Authors: Berislav Bošnjak; Saskia Catherina Stein; Stefanie Willenzon; Anne Katrin Cordes; Wolfram Puppe; Günter Bernhardt; Inga Ravens; Christiane Ritter; Christian R Schultze-Florey; Nina Gödecke; Jörg Martens; Hannah Kleine-Weber; Markus Hoffmann; Anne Cossmann; Mustafa Yilmaz; Isabelle Pink; Marius M Hoeper; Georg MN Behrens; Stefan Pöhlmann; Rainer Blasczyk; Thomas F Schulz; Reinhold Förster

    doi:10.1101/2020.07.12.20151407 Date: 2020-07-14 Source: medRxiv

    Neutralizing antibodies SERO targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) block severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) entry into cells using surface-expressed angiotensin-converting enzyme 2 (ACE2). We developed a surrogate neutralization test (sVNT) to assess at what degree serum SERO antibodies SERO interfere with the binding of SARS-CoV-2-S-RBD to ACE2. The sVNT revealed neutralizing anti-SARS-CoV-2-S antibodies SERO in the sera of 90% of mildly and 100% of severely affected coronavirus-disease MESHD-2019 (COVID-19) convalescent patients. Importantly, sVNT results correlated strongly to the results from pseudotyped- vesicular stomatitis MESHD stomatitis HP virus-vector-based neutralization assay and to levels of anti-SARS-CoV-2-S1 IgG and IgA antibodies SERO. Moreover, levels of neutralizing antibodies SERO also correlated to duration and severity of clinical symptoms, but not patient age TRANS or gender TRANS. These findings together with the sVNT will not only be important for evaluating the prevalence SERO of neutralizing antibodies SERO in a population but also for identifying promising plasma SERO donors for successful passive antibody SERO therapy.

    Replication-competent vesicular stomatitis MESHD stomatitis HP virus vaccine vector protects against SARS-CoV-2-mediated pathogenesis

    Authors: James Brett Case; Paul Rothlauf; Rita E. Chen; Natasha Kafai; Julie M. Fox; Swathi Shrihari; Broc T. McCune; Ian B. Harvey; Brittany Smith; Shamus Keeler; Louis-Marie Bloyet; Emma S Winkler; Michael J. Holtzman; Daved H. Fremont; Sean P. J. Whelan; Michael S. Diamond

    doi:10.1101/2020.07.09.196386 Date: 2020-07-10 Source: bioRxiv

    Severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) has caused millions of human infections MESHD and hundreds of thousands of deaths MESHD. Accordingly, an effective vaccine is of critical importance in mitigating coronavirus induced disease MESHD 2019 (COVID-19) and curtailing the pandemic. We developed a replication-competent vesicular stomatitis MESHD stomatitis HP virus (VSV)-based vaccine by introducing a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene (VSV-eGFP-SARS-CoV-2). Immunization of mice with VSV-eGFP-SARS-CoV-2 elicits high titers of antibodies that neutralize SARS-CoV-2 SERO infection MESHD and target the receptor binding domain that engages human angiotensin converting enzyme-2 (ACE2). Upon challenge with a human isolate of SARS-CoV-2, mice expressing human ACE2 and immunized with VSV-eGFP-SARS-CoV-2 show profoundly reduced viral infection MESHD and inflammation MESHD in the lung indicating protection against pneumonia MESHD pneumonia HP. Finally, passive transfer of sera from VSV-eGFP-SARS-CoV-2-immunized animals protects naive mice from SARS-CoV-2 challenge. These data support development of VSV-eGFP-SARS-CoV-2 as an attenuated, replication-competent vaccine against SARS-CoV-2.

    Measuring SARS-CoV-2 neutralizing antibody SERO activity using pseudotyped and chimeric viruses

    Authors: Fabian Schmidt; Yiska Weisblum; Frauke Muecksch; Hans-Heinrich Hoffmann; Eleftherios Michailidis; Julio C. C. Lorenzi; Pilar Mendoza; Magdalena Rutkowska; Eva Bednarski; Christian Gaebler; Marianna Agudelo; Alice Cho; Zijun Wang; Anna Gazumyan; Melissa Cipolla; Marina Caskey; Davide F. Robbiani; Michel C. Nussenzweig; Charles M. Rice; Theodora Hatziioannou; Paul D Bieniasz

    doi:10.1101/2020.06.08.140871 Date: 2020-06-09 Source: bioRxiv

    The emergence of SARS-CoV-2 and the ensuing explosive epidemic of COVID19 disease MESHD has generated a need for assays to rapidly and conveniently measure the antiviral activity of SARS-CoV-2-specific antibodies SERO. Here, we describe a collection of approaches based on SARS-CoV-2 spike-pseudotyped, single-cycle, replication-defective human immunodeficiency HP virus type-1 (HIV-1) and vesicular stomatitis MESHD stomatitis HP virus (VSV), as well as a replication-competent VSV/SARS-CoV-2 chimeric virus. While each surrogate virus exhibited subtle differences in the sensitivity SERO with which neutralizing activity was detected, the neutralizing activity of both convalescent plasma SERO and human monoclonal antibodies SERO measured using each virus correlated quantitatively with neutralizing activity measured using an authentic SARS-CoV-2 neutralization assay. The assays described herein are adaptable to high throughput and are useful tools in the evaluation of serologic immunity conferred by vaccination or prior SARS-CoV-2 infection MESHD, as well as the potency of convalescent plasma SERO or human monoclonal antibodies SERO.

    Development and validation of IMMUNO-COV: a high-throughput clinical assay for detecting antibodies that neutralize SARS-CoV-2 SERO

    Authors: Rianna Vandergaast; Timothy Carey; Samantha Reiter; Patrycja Lech; Clement Gnanadurai; Mulu Tesfay; Jason Buehler; Lukkana Suksanpaisan; Shruthi Naik; Bethany Brunton; Jordan Recker; Michelle Haselton; Christopher Ziegler; Anne Roesler; John R. Mills; Elitza Theel; Scott C. Weaver; Grace Rafael; Matthew M. Roforth; Clavin Jerde; Sheryl Tran; Rosa Maria Diaz; Alice Bexon; Alina Baum; Christos A. Kyratsous; Kah-Whye Peng; Stephen J. Russell

    doi:10.1101/2020.05.26.117549 Date: 2020-05-27 Source: bioRxiv

    We here describe the development and validation of IMMUNO-COV, a high-throughput clinical test to quantitatively measure SARS-CoV-2-neutralizing antibodies SERO, the specific subset of anti- SARS-CoV-2 antibodies SERO that block viral infection MESHD. The test measures the capacity of serum SERO or purified antibodies to neutralize SERO a recombinant Vesicular Stomatitis MESHD Stomatitis HP Virus (VSV) encoding the SARS-CoV-2 spike glycoprotein. This recombinant virus (VSV-SARS-CoV-2-S-{Delta}19CT) induces fusion in Vero cell monolayers, which is detected as luciferase signal using a dual split protein (DSP) reporter system. VSV-SARS-CoV-2-S-{Delta}19CT infection MESHD was blocked by monoclonal -SARS-CoV-2-spike antibodies SERO and by plasma SERO or serum SERO from SARS-CoV-2 convalescing individuals. The assay exhibited 100% specificity in validation tests, and across all tests zero false positives were detected. In blinded analyses of 230 serum samples SERO, only two unexpected results were observed based on available clinical data. We observed a perfect correlation between results from our assay and 80 samples that were also assayed using a commercially available ELISA SERO. To quantify the magnitude of the anti-viral response, we generated a calibration curve by adding stepped concentrations of -SARS-CoV-2-spike monoclonal antibody SERO to pooled SARS-CoV-2 seronegative serum SERO. Using the calibration curve and a single optimal 1:100 serum SERO test dilution, we reliably measured neutralizing antibody SERO levels in each test sample. Virus neutralization units (VNUs) calculated from the assay correlated closely (p < 0.0001) with PRNTEC50 values determined by plaque reduction neutralization test against a clinical isolate of SARS-CoV-2. Taken together, these results demonstrate that the IMMUNO-COV assay accurately quantitates SARS-CoV-2 neutralizing antibodies SERO in human sera and therefore is a potentially valuable addition to the currently available serological tests SERO. The assay can provide vital information for comparing immune responses to the various SARS-CoV-2 vaccines that are currently in development, or for evaluating donor eligibility in convalescent plasma SERO therapy studies.

    Evaluation of Neutralizing Antibodies SERO against Highly Pathogenic Coronaviruses: A Detailed Protocol for a Rapid Evaluation of Neutralizing Antibodies SERO Using Vesicular Stomatitis MESHD Stomatitis HP Virus (Vsv) Pseudovirus-Based Assay

    Authors: Sarah A. Almahboub; Abdullah Algaissi; Mohamed A. Alfaleh; M-Zaki ElAssouli; Anwar M. Hashem

    id:10.20944/preprints202005.0379.v1 Date: 2020-05-23 Source:

    Emerging highly pathogenic human coronaviruses (CoVs) represent a serious ongoing threat to the public health worldwide. The spike (S) proteins of CoVs are surface glycoproteins that facilitate viral entry into host cells via attachment to their respective cellular receptors. The S protein is believed to be a major immunogenic component of CoVs and a target for neutralizing antibodies SERO (nAbs) and most candidate vaccines. Development of a safe and convenient assay is thus urgently needed to determine the prevalence SERO of CoVs nAbs in the population, to study immune response in infected individuals, and to aid in vaccines and viral entry inhibitors evaluation. While live virus-based neutralization assays are used as gold standard serological methods to detect and measure nAbs, handling of highly pathogenic live CoVs requires strict bio-containment conditions in biosafety level-3 laboratories. On the other hand, use of replication-incompetent pseudoviruses bearing CoVs S proteins could represent a safe and useful method to detect nAbs in serum samples SERO under biosafety level-2 conditions. Here, we describe a detailed protocol of a safe and convenient assay to generate vesicular stomatitis MESHD stomatitis HP virus (VSV)-based pseudoviruses to evaluate and measure nAbs against highly pathogenic CoVs. The protocol covers methods to produce VSV pseudovirus bearing the S protein of the Middle East respiratory syndrome MESHD-CoV (MERS-CoV) and the severe acute respiratory syndrome MESHD-CoV-2 (SARS-CoV-2), pseudovirus titration, and pseudovirus neutralizing assay. Such assay could be adapted by different laboratories and researchers working on highly pathogenic CoVs without the need to handle live viruses in biosafety level-3 environment.

    Effective Screening of SARS-CoV-2 Neutralizing Antibodies SERO in Patient Serum SERO using Lentivirus Particles Pseudotyped with SARS-CoV-2 Spike Glycoprotein

    Authors: Ritesh Tandon; Dipanwita Mitra; Poonam Sharma; Stephan J Stray; John T Bates; Gailen D Marshall

    doi:10.1101/2020.05.21.20108951 Date: 2020-05-23 Source: medRxiv

    Pseuodotyped particles have significant importance and use in virology as tools for studying the biology of highly pathogenic viruses in a lower biosafety environment. The biological, chemical, and serological studies of the recently emerged SARS-CoV-2 will be greatly aided by the development and optimization of a suitable pseudotyping system. Here, we pseudotyped the SARS-CoV-2 Spike glycoprotein (SPG) on a retroviral (MMLV) as well as a third generation lentiviral (pLV) vector and tested the transduction efficiency in several mammalian cell lines expressing SARS-CoV-2 receptor hACE2. While MMLV pseudotyped the vesicular stomatitis MESHD stomatitis HP virus G glycoprotein (VSV-G) efficiently, it could not pseudotype SPG. In contrast, pLV pseudotyped both glycoproteins efficiently; however, much higher titers of pLV-G particles were produced. Among all the tested mammalian cells, 293Ts expressing hACE2 were most efficiently transduced using the pLV-S system. The pLV-S particles were efficiently neutralized by diluted serum SERO (>:640) from a recently recovered COVID-19 patient who showed high SARS-CoV-2 specific IgM and IgG levels. In summary, pLV-S pseudotyped virus provides a valid screening tool for the presence of anti SARS-CoV-2 specific neutralizing antibodies SERO in convalescent patient serum SERO.

    A replication-competent vesicular stomatitis MESHD stomatitis HP virus for studies of SARS-CoV-2 spike-mediated cell entry and its inhibition

    Authors: M Eugenia Dieterle; Denise Haslwanter; Robert H Bortz III; Ariel S Wirchnianski; Gorka Lasso; Olivia Vergnolle; Shawn A Abbasi; J Maximilian Fels; Ethan Laudermilch; Catalina Florez; Amanda Mengotto; Duncan Kimmel; Ryan J Malonis; George Georgiev; Jose Quiroz; Jason Barnhill; Liise-Anne Pirofski; Johanna P Daily; John M Dye; Jonathan R Lai; Andrew S Herbert; Kartik Chandran; Rohit K Jangra

    doi:10.1101/2020.05.20.105247 Date: 2020-05-20 Source: bioRxiv

    There is an urgent need for vaccines and therapeutics to prevent and treat COVID-19. Rapid SARS-CoV-2 countermeasure development is contingent on the availability of robust, scalable, and readily deployable surrogate viral assays to screen antiviral humoral responses, and define correlates of immune protection, and to down-select candidate antivirals. Here, we describe a highly infectious recombinant vesicular stomatitis MESHD stomatitis HP virus bearing the SARS-CoV-2 spike glycoprotein S as its sole entry glycoprotein that closely resembles the authentic agent in its entry-related properties. We show that the neutralizing activities of a large panel of COVID-19 convalescent sera can be assessed in high-throughput fluorescent reporter assay with rVSV-SARS-CoV-2 S and that neutralization of the rVSV and authentic SARS-CoV-2 by spike-specific antibodies SERO in these antisera is highly correlated. Our findings underscore the utility of rVSV-SARS-CoV-2 S for the development of spike-specific vaccines and therapeutics and for mechanistic studies of viral entry and its inhibition.

    Neutralizing antibody SERO and soluble ACE2 inhibition of a replication-competent VSV-SARS-CoV-2 and a clinical isolate of SARS-CoV-2.

    Authors: James Brett Case; Paul W Rothlauf; Rita E Chen; Zhuoming Liu; Haiyan Zhao; Arthur S Kim; Louis-Marie Bloyet; Qiru Zeng; Stephen Tahan; Lindsay Droit; Ma. Xenia G. Ilagan; Michael A Tartell; Gaya K Amarasinghe; Jeffrey P Henderson; Shane Miersch; Mart Ustav; Sachdev Sidhu; Herbert W Virgin; David Wang; Siyuan Ding; Davide Corti; Elitza S Theel; Daved H Fremont; Michael S Diamond; Sean P. J. Whelan

    doi:10.1101/2020.05.18.102038 Date: 2020-05-18 Source: bioRxiv

    Antibody SERO-based interventions against SARS-CoV-2 could limit morbidity, mortality, and possibly disrupt epidemic transmission TRANS. An anticipated correlate of such countermeasures is the level of neutralizing antibodies SERO against the SARS-CoV-2 spike protein, yet there is no consensus as to which assay should be used for such measurements. Using an infectious molecular clone of vesicular stomatitis MESHD stomatitis HP virus (VSV) that expresses eGFP as a marker of infection MESHD, we replaced the glycoprotein gene (G) with the spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and developed a high-throughput imaging-based neutralization assay at biosafety level 2. We also developed a focus reduction neutralization test with a clinical isolate of SARS-CoV-2 at biosafety level 3. We compared the neutralizing activities of monoclonal and polyclonal antibody SERO preparations, as well as ACE2-Fc soluble decoy protein in both assays and find an exceptionally high degree of concordance. The two assays will help define correlates of protection for antibody SERO-based countermeasures including therapeutic antibodies SERO, immune {gamma}-globulin or plasma SERO preparations, and vaccines against SARS-CoV-2. Replication-competent VSV-eGFP-SARS-CoV-2 provides a rapid assay for testing inhibitors of SARS-CoV-2 mediated entry that can be performed in 7.5 hours under reduced biosafety containment.

    Robust neutralization assay based on SARS-CoV-2 S-bearing vesicular stomatitis MESHD stomatitis HP virus (VSV) pseudovirus and ACE2-overexpressed BHK21 cells

    Authors: Hualong Xiong; Yangtao Wu; Jiali Cao; Ren Yang; Jian Ma; Xiaoyang Qiao; Xiangyang Yao; Baohui Zhang; Yali Zhang; Wangheng Hou; Yang Shi; Jingjing Xu; Liang Zhang; Shaojuan Wang; Baorong Fu; Ting Yang; Shengxiang Ge; Jun Zhang; Quan Yuan; Baoying Huang; Zhiyong Li; Tianying Zhang; Ningshao Xia

    doi:10.1101/2020.04.08.026948 Date: 2020-04-09 Source: bioRxiv

    The global pandemic of Coronavirus disease MESHD 2019 (COVID-19) is a disaster for human society. A convenient and reliable in vitro neutralization assay is very important for the development of neutralizing antibodies SERO, vaccines and other inhibitors. In this study, G protein-deficient vesicular stomatitis MESHD stomatitis HP virus (VSVdG) bearing full-length and truncated spike (S) protein of SARS-CoV-2 were evaluated. The virus packaging efficiency of VSV-SARS-CoV-2-Sdel18 (S with C-terminal 18 amino acid truncation) is much higher than VSV-SARS-CoV-2-S. A neutralization assay for antibody SERO screening and serum SERO neutralizing titer quantification was established based on VSV-SARS-CoV-2-Sdel18 pseudovirus and human angiotensin-converting enzyme 2 (ACE2) overexpressed BHK21 cell (BHK21-hACE2). The experimental results can be obtained by automatically counting EGFP positive cell number at 12 hours after infection MESHD, making the assay convenient and high-throughput. The serum SERO neutralizing titer of COVID-19 convalescent patients measured by VSV-SARS-CoV-2-Sdel18 pseudovirus assay has a good correlation with live SARS-CoV-2 assay. Seven neutralizing monoclonal antibodies SERO targeting receptor binding domain (RBD) of SARS-CoV-2-S were obtained. This efficient and reliable pseudovirus assay model could facilitate the development of new drugs and vaccines.

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MeSH Disease
Human Phenotype

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