Corpus overview


Overview

MeSH Disease

Human Phenotype

Stomatitis (6)

Pneumonia (1)

Pain (1)


Transmission

There are no transmission terms in the subcorpus


Seroprevalence
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    In silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and SARS-CoV-2 Spike MESHD protein

    Authors: Samantha Perez-Miller; Marcel Patek; Aubin Moutal; Carly R Cabel; Curtis A. Thorne; Samuel K Campos; Rajesh Khanna

    doi:10.1101/2020.09.22.308783 Date: 2020-09-23 Source: bioRxiv

    Neuropilin-1 (NRP-1) is a multifunctional transmembrane receptor for ligands that affect developmental axonal growth MESHD and angiogenesis. In addition to a role in cancer MESHD, NRP-1 is a reported entry point for several viruses, including severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), the causal agent of coronavirus disease MESHD 2019 (COVID-19). The furin cleavage product of SARS-CoV-2 Spike MESHD protein takes advantage of the vascular endothelial growth factor A (VEGF-A) binding site on NRP-1 which accommodates a polybasic stretch ending in a C-terminal arginine. This site has long been a focus of drug discovery efforts for cancer MESHD therapeutics. We recently showed that interruption of the VEGF-A/NRP-1 signaling pathway ameliorates neuropathic pain MESHD pain HP and hypothesize that interference of this pathway by SARS-CoV-2 spike protein interferes with pain HP pain MESHD signaling. Here, we report hits from a small molecule and natural product screen of nearly 0.5 million compounds targeting the VEGF-A binding site on NRP-1. We identified nine chemical series with lead- or drug-like physico-chemical properties. Using an ELISA SERO, we demonstrate that six compounds disrupt VEGF-A-NRP-1 binding more effectively than EG00229, a known NRP-1 inhibitor. Secondary validation in cells revealed that almost all tested compounds inhibited VEGF-A triggered VEGFR2 phosphorylation. Two compounds displayed robust inhibition of a recombinant vesicular stomatitis MESHD stomatitis HP virus protein that utilizes the SARS-CoV-2 Spike for entry and fusion. These compounds represent a first step in a renewed effort to develop small molecule inhibitors of the VEGF-A/NRP-1 signaling for the treatment of neuropathic pain MESHD pain HP and cancer MESHD with the added potential of inhibiting SARS-CoV-2 virus entry.

    SARS-CoV-2 ORF9b Antagonizes Type I and III Interferons by Targeting Multiple Components of RIG-I/MDA-5-MAVS, TLR3-TRIF, and cGAS-STING Signaling Pathways

    Authors: Lulu Han; Meng-Wei Zhuang; Yi Zheng; Jing Zhang; Mei-Ling Nan; Pei-Hui Wang; Chengjiang Gao; Katie G Beauregard; Ying Zhang; Megan Cleary; Samantha Xu; Xiao Yao; Purvish P Patel; Tatiana Plavina; David H Wilson; Lei Chang; Kim M Kaiser; Jacob Natterman; Susanne V Schmidt; Eicke Latz; Kevin Hrusovsky; Dawn Mattoon; Andrew J Ball; Saurabh Gombar; Robert Tibshirani; Benjamin A Pinsky; Scott D Boyd

    doi:10.1101/2020.08.16.252973 Date: 2020-08-17 Source: bioRxiv

    Severe acute respiratory syndrome MESHD corona-virus 2 (SARS-CoV-2), the etiologic agent of the coronavirus disease MESHD 2019 (COVID-19), has a catastrophic effect on human health and society. Clinical findings indicated that the suppression of innate antiviral immunity, especially the type I and III interferon (IFN) production, contributes to the pathogenesis of COVID-19. However, how SARS-CoV-2 evades antiviral immunity still needs further investigations. Here, we reported that the open reading frame 9b (ORF9b) protein encoded by the SARS-CoV-2 genome inhibits the activation of type I and III IFN response by targeting multiple molecules of innate antiviral signaling pathways. SARS-CoV-2 ORF9b impaired the induction of type I and III IFNs by Sendai virus or the dsRNA mimic poly (I:C). SARS-CoV-2 ORF9b inhibits the activation of type I and III IFNs induced by the components of cytosolic dsRNA-sensing pathways of RIG-I/MDA5-MAVS signaling, including RIG-I, MDA-5, MAVS, TBK1, and IKK{varepsilon} rather than IRF3-5D, the active form of IRF3. SARS-CoV-2 ORF9b also suppressed the induction of type I and III IFNs by TRIF and STING, the adaptor protein of endosome RNA-sensing pathway of TLR3-TRIF signaling and the adaptor protein of cytosolic DNA-sensing pathway of cGAS-STING signaling, respectively. Mechanistically, SARS-CoV-2 ORF9b protein interacts with RIG-I, MDA-5, MAVS, TRIF, STING, TBK1, and prevents TBK1 phosphorylation, thus impeding the phosphorylation and nuclear trans-localization of IRF3 activation. Overexpression of SARS-CoV-2 ORF9b facilitates the replication of the vesicular stomatitis virus MESHD stomatitis HP virus. Therefore, SARS-CoV-2 ORF9b negatively regulates antiviral immunity, thus, facilitate virus replication. This study contributes to our understanding of the molecular mechanism of how SARS-CoV-2 impaired antiviral immunity and providing an essential clue to the pathogenesis of COVID-19.

    Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (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 coronavirus 2 MESHD (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 virus MESHD stomatitis HP virus ( VSV MESHD). 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.

    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 coronavirus 2 MESHD (SARS-CoV-2) has caused millions of human infections MESHD and hundreds of thousands of deaths. Accordingly, an effective vaccine is of critical importance in mitigating coronavirus induced disease 2019 (COVID-19) and curtailing the pandemic. We developed a replication-competent vesicular stomatitis virus MESHD stomatitis HP virus ( VSV MESHD)-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 MESHD). Immunization of mice with VSV-eGFP-SARS-CoV-2 MESHD elicits high titers of antibodies that neutralize SARS-CoV-2 SERO SARS-CoV-2 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 MESHD show profoundly reduced viral infection MESHD and inflammation MESHD in the lung indicating protection against pneumonia HP pneumonia MESHD. Finally, passive transfer of sera from VSV MESHD-eGFP-SARS-CoV-2-immunized animals protects naive mice from SARS-CoV-2 challenge. These data support development of VSV-eGFP-SARS-CoV-2 MESHD as an attenuated, replication-competent vaccine against SARS-CoV-2.

    Evaluation of Neutralizing Antibodies SERO against Highly Pathogenic Coronaviruses: A Detailed Protocol for a Rapid Evaluation of Neutralizing Antibodies SERO Using Vesicular Stomatitis Virus MESHD Stomatitis HP Virus ( Vsv MESHD) 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: Preprints.org

    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 virus MESHD stomatitis HP virus ( VSV MESHD)-based pseudoviruses to evaluate and measure nAbs against highly pathogenic CoVs. The protocol covers methods to produce VSV MESHD pseudovirus bearing the S protein of the Middle East respiratory syndrome-CoV (MERS-CoV) MESHD and the severe acute respiratory syndrome-CoV-2 MESHD (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.

    Robust neutralization assay based on SARS-CoV-2 S-bearing vesicular stomatitis virus 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 virus 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 MESHD-2-Sdel18 (S with C-terminal 18 amino acid truncation) is much higher than VSV-SARS-CoV-2-S MESHD. 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
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Transmission
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