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    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.

    Identification of key genes and pathways in the hPSC-derived lungs infected by the SARS-CoV-2

    Authors: Hanming Gu; Gongsheng Yuan

    doi:10.21203/rs.3.rs-114578/v1 Date: 2020-11-23 Source: ResearchSquare

    Coronavirus disease 2019 MESHD ( COVID-19 MESHD) is caused by the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), which has led to numerous infections MESHD and deaths MESHD in the world. Our research is to explore the differentially expressed genes (DEGs) and signaling pathways in hPSC-derived lungs by using a bioinformatics method to clarify their potential pathogenesis. The gene expression profile of GSE155241 dataset was originally created by using an Illumina NovaSeq 6000 (Homo sapiens) platform. Functional categories and significant pathways were identified by the KEGG and GO analysis. The results suggested that brain disorders MESHD and mitochondrial dysfunctions MESHD are the main signaling pathways affected by the SARS-CoV-2 infection MESHD. Furthermore, key genes e PROTEIN.g. CDC20 HGNC, NCBP1 HGNC and inhibitors e.g. MEK1 HGNC-2-inhibitor, tivozanib may paly critical roles in COVID-19 MESHD. Therefore, our study provides insights into the treatment of COVID-19 MESHD and related disorders.

    SARS-CoV-2 antibody signatures for predicting the outcome of COVID-19 MESHD

    Authors: Qing Lei; Caizheng Yu; Yang Li; Hongyan Hou; Zhaowei Xu; Meian He; Ziyong Sun; Feng Wang; Sheng-ce Tao; Xionglin Fan

    doi:10.1101/2020.11.10.20228890 Date: 2020-11-13 Source: medRxiv

    The COIVD-19 global pandemic is far from ending. There is an urgent need to identify applicable biomarkers for predicting the outcome of COVID-19 MESHD. Growing evidences have revealed that SARS-CoV-2 specific antibodies remain elevated with disease progression and severity in COIVD-19 patients. We assumed that antibodies may serve as biomarkers for predicting disease outcome. By taking advantage of a newly developed SARS-CoV-2 proteome microarray, we surveyed IgM/ IgG responses against 20 SARS-CoV-2 proteins in 1,034 hospitalized COVID-19 MESHD patients on admission, who were followed till 66 days. The microarray results were correlated with clinical information, laboratory test results and patient outcomes. Cox proportional hazards model was used to explore the association between SARS-CoV-2 specific antibodies and COVID-19 MESHD mortality. We found that high level of IgM against ORF7b PROTEIN at the time of hospitalization is an independent predictor of patient survival (p trend = 0.002), while levels of IgG responses to 6 non-structural proteins PROTEIN and 1 accessory protein, i. e PROTEIN., NSP4 HGNC NSP4 PROTEIN, NSP7 PROTEIN, NSP9 PROTEIN, NSP10 PROTEIN, RdRp PROTEIN ( NSP12 PROTEIN), NSP14 PROTEIN, and ORF3b PROTEIN, possess significant predictive power for patient death MESHD, even after further adjustments for demographics, comorbidities, and common laboratory markers for disease severity (all with p trend < 0.05). Spline regression analysis indicated that the correlation between ORF7b PROTEIN IgM, NSP9 PROTEIN IgG, and NSP10 PROTEIN IgG and risk of COVID-19 MESHD mortality is linear (p = 0.0013, 0.0073 and 0.0003, respectively). Their AUCs for predictions, determined by computational cross-validations (validation1), were 0.74 (cut-off = 7.59), 0.66 (cut-off = 9.13), and 0.68 (cut-off = 6.29), respectively. Further validations were conducted in the second and third serial samples of these cases (validation2A, n = 633, validation2B, n = 382), with high accuracy of prediction for outcome. These findings have important implications for improving clinical management, and especially for developing medical interventions and vaccines.

    Engineering Novel Epitope-Based Subunit Vaccine against SARS-CoV-2 by Exploring the Immunoinformatics Approach

    Authors: Bishajit Sarkar; Md. Asad Ullah; Yusha Araf; Mohammad Shahedur Rahman

    id:10.20944/preprints202009.0631.v1 Date: 2020-09-26 Source: Preprints.org

    As the number of infections and deaths MESHD caused by the recent COVID-19 MESHD COVID-19 MESHD pandemic is increasing dramatically day-by-day, scientists are rushing towards developing possible counter-measures to fight the deadly virus, SARS-CoV-2. Although many efforts have already been put forward for designing and developing potential vaccines, however, most of them are proved to possess negative consequences. Therefore, in this study, the methods of immunoinformatics were exploited to design novel epitope-based subunit vaccine against the SARS-CoV-2, targeting four essential proteins of the virus i.e., spike glycoprotein PROTEIN, nucleocapsid phosphoprotein, membrane glycoprotein PROTEIN, and envelope protein PROTEIN. The highly antigenic, non-allergenic, non-toxic, non-human homolog and 100% conserved (across other isolates from different regions of the world) epitopes were used for constructing the vaccine. In total, fourteen CTL epitopes and eighteen HTL epitopes were used to construct the vaccine. Thereafter, several in silico validations i.e., the molecular docking, molecular dynamics simulation (including the RMSF and RMSD studies), and immune simulation studies were also performed which predicted that the designed vaccine should be quite safe, effective, and stable within the biological environment. Finally, in silico cloning and codon adaptation studies were also conducted to design an effective mass production strategy of the vaccine. However, more in vivo and in vitro studies are required on the predicted vaccine to finally validate its safety and efficacy.

    Structure/epitope-based immunoinformatics analysis of structural proteins of 2019 novel coronavirus

    Authors: Yuwei Li; Mi Mao; Liteng Yang; Xizhuo Sun; Nanshan Zhong; Zhigang Liu

    doi:10.21203/rs.3.rs-50740/v1 Date: 2020-07-29 Source: ResearchSquare

    The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 81,400 laboratory-confirmed human infections, including 3261 deaths MESHD, posing a serious threat to human health. Currently, however, there is no specific antiviral treatment or vaccine. To identify immunodominant peptides for designing global peptide vaccine for combating the infections caused by 2019-nCoV, the structure and immunogenicity of 2019-nCoV structural protein were analyzed by bioinformatics tools. 33 B-cell epitopes and 39 T-cell epitopes were determined in four structural proteins via different immunoinformatic tools in which include spike protein PROTEIN (22 B-cell epitopes, 25 T-cell epitopes ), nucleocapsid protein PROTEIN (7 B-cell epitopes, 6 T-cell epitopes), membrane protein (2 B-cell epitopes, 7 T-cell epitopes), and envelope protein PROTEIN (2 B-cell epitopes, 1T-cell epitopes), respectively. The proportion of epitope residues in primary sequence was used to determine the antigenicity and immunogenicity of proteins. The envelope protein PROTEIN has the largest antigenicity in which residue coverage of B-cell epitopes is 24%. The membrane protein possesses the largest immunogenicity in which residue coverage of T-cell epitopes is 55.86%. The reason that immune storm was caused by 2019-nCoV maybe that the membrane and envelope protein PROTEIN expressed plentifully in cell infected. Further, studies involving experimental validation of these predicted epitopes is warranted to ensure the potential of B-cells and T-cells stimulation for their effective use as vaccine candidates. These findings provide the basis for starting further studies on the pathogenesis, and optimizing the design of diagnostic, antiviral and vaccination strategies for this emerging infection MESHD.

    Genetic diversity among SARS-CoV2 strains in South America may impact performance of Molecular detection

    Authors: Juan David Ramirez; Marina Munoz; Carolina Hernandez; Carolina Florez; Sergio Gomez; Angelica Rico; Lisseth Pardo; Esther C Barros; Alberto Paniz-Mondolfi

    doi:10.1101/2020.06.18.20134759 Date: 2020-06-22 Source: medRxiv

    Since its emergence in Wuhan (China) on December 2019 the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide. After its arrival in South America in February 2020 the virus has expanded throughout the region infecting over 900,000 individuals with approximately 41,000 reported deaths MESHD to date. In response to the rapidly growing number of cases, a number of different primer-probe sets have been developed. However, despite being highly specific most of these primer-probe sets are known to exhibit variable sensitivity. Currently, there are more than 700 SARS-CoV2 whole genome sequences deposited in databases from Brazil, Chile, Ecuador, Colombia, Uruguay, Peru and Argentina. To test how regional viral diversity may impact oligo binding sites and affect test performance, we reviewed all available primer-probe sets targeting the E, N and RdRp PROTEIN genes against available South American SARS-CoV-2 genomes checking for nucleotide variations in annealing sites. Results from this in silico analysis showed no nucleotide variations on the E-gene PROTEIN target region, in contrast to the N and RdRp PROTEIN genes which showed massive nucleotide variations within oligo binding sites. In lines with previous data, our results suggest that E-gene PROTEIN stands as the most conserved and reliable target when considering single-gene target testing for molecular diagnosis of SARS-CoV-2 in South America.

    Functional pangenome analysis provides insights into the origin, function and pathways to therapy of SARS-CoV-2 coronavirus

    Authors: Intikhab Alam; Allan K Kamau; Maxat Kulmanov; Stefan T Arold; Arnab T Pain; Takashi Gojobori; Carlos M. Duarte

    doi:10.1101/2020.02.17.952895 Date: 2020-02-21 Source: bioRxiv

    The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S PROTEIN) of this virus enables binding to the human receptor ACE2 HGNC, and hence presents a prime target for vaccines preventing viral entry into host cells1. The S proteins PROTEIN from SARS-CoV-1 and SARS-CoV-2 MESHD are similar2, but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1-specific neutralizing antibodies to inhibit SARS-CoV-23. Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E PROTEIN shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema MESHD in lungs causing the acute respiratory distress syndrome MESHD ( ARDS MESHD)4-6, the leading cause of death MESHD in SARS-CoV-1 and SARS-CoV-2 infection7 MESHD SARS-CoV-2 infection MESHD7,8. However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E PROTEIN, either acting upon the ion channel (Amantadine and Hexamethylene amiloride9,10) or the PBM (SB2035805), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E PROTEIN inhibits development of ARDS in vivo. Given that our results demonstrate that the protein E PROTEIN subcluster for the SARS clade is quasi-identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein PROTEIN inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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