Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (689)

NSP5 (33)

ProteinN (29)

ProteinS1 (26)

ComplexRdRp (23)


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SARS-CoV-2 Proteins
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    Molecular Profiling of COVID-19 MESHD Autopsies Uncovers Novel Disease Mechanisms

    Authors: Elisabet Pujadas; Michael Beaumont; Hardik Shah; Nadine Schrode; Nancy Francoeur; Sanjana Shroff; Clare Bryce; Zachary Grimes; Jill Gregory; Ryan Donnelly; Mary Fowkes; Kristin Beaumont; Robert Sebra; Carlos Cordon-Cardo

    doi:10.1101/2021.04.04.21253205 Date: 2021-04-07 Source: medRxiv

    Background: Current understanding of COVID-19 MESHD pathophysiology is limited by disease heterogeneity, complexity, and a paucity of studies evaluating patient tissues with advanced molecular tools. Methods: Autopsy tissues from two COVID-19 MESHD patients, one of whom died after a month-long hospitalization with multi-organ involvement while the other died after a few days of respiratory symptoms, were evaluated using multi-scale RNASeq methods (bulk, single-nuclei, and spatial RNASeq next-generation sequencing) to provide unprecedented molecular resolution of COVID-19 MESHD induced damage. Findings: Comparison of infected/uninfected tissues revealed four major regulatory pathways. Effectors within these pathways could constitute novel therapeutic targets, including the complement receptor C3AR1 HGNC, calcitonin-like receptor or decorin. Single-nuclei RNA sequencing of olfactory bulb and prefrontal cortex highlighted remarkable diversity of coronavirus receptors. Angiotensin I converting enzyme 2 HGNC was rarely expressed, while Basignin showed diffuse expression, and alanyl aminopeptidase was associated with vascular/mesenchymal cell types. Comparison of lung and lymph node tissues from patients with different symptomatology with Digital Spatial Profiling resulted in distinct molecular phenotypes. Interpretation: COVID-19 MESHD is a far more complex and heterogeneous disease than initially anticipated. Evaluation of COVID-19 MESHD rapid autopsy tissues with advanced molecular techniques can identify pathways and effectors at play in individual patients, measure the staggering diversity of receptors in specific brain areas and other well-defined tissue compartments at the single-cell level, and help dissect differences driving diverging clinical courses among patients. Extension of this approach to larger datasets will substantially advance the understanding of the mechanisms behind COVID-19 MESHD pathophysiology. Funding: No external funding was used in this study.

    Mutations in the B.1.1.7 SARS-CoV-2 spike PROTEIN protein reduce receptor-binding affinity and induce a flexible link to the fusion peptide

    Authors: Eileen Socher; Marcus Conrad; Lukas Heger; Friedrich Paulsen; Heinrich Sicht; Friederike Zunke; Philipp Arnold

    doi:10.1101/2021.04.06.438584 Date: 2021-04-06 Source: bioRxiv

    The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. A number of single amino acid exchanges and deletions within the trimeric viral spike protein PROTEIN characterize this new SARS-CoV-2 variant. Crucial for viral entry into the host cell is the interaction of the spike protein PROTEIN with the cell surface receptor angiotensin-converting enzyme 2 ( ACE2 HGNC) as well as integration of the viral fusion peptide into the host membrane. Respective amino acid exchanges within the SARS-CoV-2 variant B.1.1.7 affect inter-monomeric contact sites within the spike protein PROTEIN (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the viral spike protein PROTEIN. However, the molecular consequences of mutations within B.1.1.7 on spike protein PROTEIN dynamics and stability, the fusion peptide, and ACE2 HGNC binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein PROTEIN trimer. In addition to reduced flexibility in the N-terminal domain of the spike protein PROTEIN, we found increased flexibility in direct spatial proximity of the fusion peptide. This increase in flexibility is due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7 found in pre- and post-cleavage state at the S2 site. Our results also imply a reduced binding affinity for B.1.1.7 with ACE2 HGNC, as the N501Y mutation restructures the RBD- ACE2 HGNC interface, significantly decreasing the linear interaction energy between the RBD and ACE2 HGNC. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD- ACE2 HGNC interface, which, in combination, might explain the higher infectivity of B.1.1.7. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7, but also other highly contagious SARS-CoV-2 variants, as many of them likewise exhibit a combination of the D614G and N501Y mutation.

    The Up state of the SARS-COV-2 Spike homotrimer favors an increased virulence for new variants

    Authors: Carolina Correa Giron; Aatto Laaksonen; Fernando Luis Barroso da Silva

    doi:10.1101/2021.04.05.438465 Date: 2021-04-06 Source: bioRxiv

    The COVID-19 pandemic MESHD has spread widely worldwide. However, as soon as the vaccines were released - the only scientifically verified and efficient therapeutic option thus far - a few mutations combined into variants of SARS-CoV-2 that are more transmissible and virulent emerged raising doubts about their efficiency. Therefore, this work aims to explain possible molecular mechanisms responsible for the increased transmissibility and the increased rate of hospitalizations related to the new variants. A combination of theoretical methods was employed. Constant-pH Monte Carlo simulations were carried out to quantify the stability of several spike trimeric structures at different conformational states and the free energy of interactions between the receptor binding domain (RBD) and Angiotensin Converting Enzyme 2 HGNC ( ACE2 HGNC) for the most worrying variants. Electrostatic epitopes were mapped using the PROCEEDpKa method. These analyses showed that the increased virulence is more likely to be due to the improved stability to the S trimer in the opened state (the one in which the virus can interact with the cellular receptor ACE2 HGNC) than due to alterations in the complexation RBD- ACE2 HGNC, once the difference observed in the free energy values is small. Conversely, the South African variant (B.1.351), when compared with the wild type SARS-CoV-2, is much more stable in the opened state (either with one or two RBDs in the up position) than in the closed state (with the three RBDs in the down position). Such results contribute to the understanding of the natural history of disease and also to indicate possible strategies to both develop new therapeutic molecules and to adjust the vaccine doses for a higher production of B cells antibodies.

    An emerging SARS-CoV-2 mutant evading cellular immunity and increasing viral infectivity

    Authors: Chihiro Motozono; Mako Toyoda; Jiri Zahradnik; Terumasa Ikeda; Akatsuki Saito; Toong Seng Tan; Isaac Ngare; Hesham Nasser; Izumi Kimura; Keiya Uriu; Yusuke Kosugi; Shiho Torii; Akiko Yonekawa; Nobuyuki Shimono; Yoji Nagasaki; Rumi Minami; Takashi Toya; Noritaka Sekiya; Takasuke Fukuhara; Yoshiharu Matsuura; Gideon Schreiber; - The Genotype to Phenotype Japan (G2P-Japan) consortium; So Nakagawa; Takamasa Ueno; Kei Sato

    doi:10.1101/2021.04.02.438288 Date: 2021-04-05 Source: bioRxiv

    During the current SARS-CoV-2 pandemic that is devastating the modern societies worldwide, many variants that naturally acquire multiple mutations have emerged. Emerging mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has recently been investigated, that to human leukocyte antigen (HLA)-restricted cellular immunity remains unaddressed. Here we demonstrate that two recently emerging mutants in the receptor binding domain of the SARS-CoV-2 spike PROTEIN protein, L452R (in B.1.427/429) and Y453F (in B.1.298), can escape from the HLA-24-restricted cellular immunity. These mutations reinforce the affinity to viral receptor ACE2 HGNC, and notably, the L452R mutation increases protein stability, viral infectivity, and potentially promotes viral replication. Our data suggest that the HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes, and the escape from cellular immunity can be a further threat of the SARS-CoV-2 pandemic.

    Membrane lectins enhance SARS-CoV-2 infection MESHD and influence the neutralizing activity of different classes of antibodies

    Authors: Florian A. Lempp; Leah Soriaga; Martin Montiel-Ruiz; Fabio Benigni; Julia Noack; Young-Jun Park; Siro Bianchi; Alexandra C. Walls; John E. Bowen; Jiayi Zhou; Hanna Kaiser; Maria Agostini; Marcel Meury; Exequiel Dellota Jr.; Stefano Jaconi; Elisabetta Cameroni; Herbert W. Virgin; Antonio Lanzavecchia; David Veesler; Lisa Purcell; Amalio Telenti; Davide Corti

    doi:10.1101/2021.04.03.438258 Date: 2021-04-04 Source: bioRxiv

    Investigating the mechanisms of SARS-CoV-2 cellular infection MESHD is key to better understand COVID-19 MESHD immunity and pathogenesis. Infection, which involves both cell attachment and membrane fusion, relies on the ACE2 HGNC receptor that is paradoxically found at low levels in the respiratory tract, suggesting that additional mechanisms facilitating infection may exist. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN HGNC and the sialic acid-binding Ig-like lectin 1 HGNC ( SIGLEC1 HGNC) function as auxiliary receptors by enhancing ACE2 HGNC-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the N-terminal domain ( NTD HGNC) or to the conserved proteoglycan site at the base of the Receptor Binding Domain (RBD), while poorly neutralizing infection of ACE2 HGNC over-expressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the Receptor Binding Motif ( RBM HGNC), while potently neutralizing infection of ACE2 HGNC over-expressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN HGNC and trigger fusogenic rearrangement of the spike promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2 HGNC-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.

    Smoking modulates different secretory subpopulations expressing SARS-CoV-2 entry genes in the nasal and bronchial airways

    Authors: Ke Xu; Xingyi Shi; Chris Husted; Rui Hong; Yichen Wang; Boting Ning; Travis Sullivan; Kimberly M Rieger-Christ; Fenghai Duan; Helga Marques; Adam C Gower; Xiaohui Xiao; Hanqiao Liu; Gang Liu; Grant Duclos; Avrum Spira; Sarah A Mazzilli; Ehab Billatos; Marc E Lenburg; Joshua D Campbell; Jennifer Beane

    doi:10.1101/2021.03.30.21254564 Date: 2021-04-04 Source: medRxiv

    Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) is caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), which infects host cells with help from the Viral Entry (VE) proteins ACE2 HGNC, TMPRSS2 HGNC, and CTSL HGNC. Proposed risk factors for viral infection MESHD, as well as the rate of disease progression, include age, sex, chronic obstructive pulmonary disease MESHD, cancer MESHD, and cigarette smoking. To investigate whether the proposed risk factors increase viral infection MESHD by modulation of the VE genes, we examined gene expression profiles of 796 nasal and 1,673 bronchial samples across four lung cancer MESHD screening cohorts containing individuals without COVID-19 MESHD. Smoking was the only clinical factor reproducibly associated with the expression of any VE gene across cohorts. ACE2 HGNC expression was significantly up-regulated with smoking in the bronchus but significantly down-regulated with smoking in the nose. Furthermore, expression of individual VE genes were not correlated between paired nasal and bronchial samples from the same patients. Single-cell RNA-seq of nasal brushings revealed that an ACE2 HGNC gene module was detected in a variety of nasal secretory cells with the highest expression in the C15orf48 HGNC+ secretory cells, while a TMPRSS2 HGNC gene module was most highly expressed in nasal keratinizing epithelial cells. In contrast, single-cell RNA-seq of bronchial brushings revealed that ACE2 HGNC and TMPRSS2 HGNC gene modules were most enriched in MUC5AC HGNC+ bronchial goblet cells. The CTSL HGNC gene module was highly expressed in immune populations of both nasal and bronchial brushings. Deconvolution of bulk RNA-seq showed that the proportion of MUC5AC HGNC+ goblet cells was increased in current smokers in both the nose and bronchus but proportions of nasal keratinizing epithelial cells, C15orf48 HGNC+ secretory cells, and immune cells were not associated with smoking status. The complex association between VE gene expression and smoking in the nasal and bronchial epithelium revealed by our results may partially explain conflicting reports on the association between smoking and SARS-CoV-2 infection MESHD.

    Bioinformatics analysis of SARS-CoV-2 RBD mutant variants and insights into antibody and ACE2 HGNC receptor binding

    Authors: Prashant Ranjan; Neha; Chandra Devi; Parimal Das

    doi:10.1101/2021.04.03.438113 Date: 2021-04-04 Source: bioRxiv

    Prevailing COVID-19 MESHD vaccines are based on the spike protein PROTEIN of earlier SARS-CoV-2 strain that emerged in Wuhan, China. Continuously evolving nature of SARS-CoV-2 resulting emergence of new variant/s raise the risk of immune absconds. Several RBD (receptor-binding domain) variants have been reported to affect the vaccine efficacy considerably. In the present study, we performed in silico structural analysis of spike protein PROTEIN of double mutant (L452R & E484Q), a new variant of SARS-CoV-2 recently reported in India along with K417G variants and earlier reported RBD variants and found structural changes in RBD region after comparing with the wild type. Comparison of the binding affinity of the double mutant and earlier reported RBD variant for ACE2 HGNC (angiotensin 2 altered enzymes) receptor and CR3022 antibody with the wild-type strain revealed the lowest binding affinity of the double mutant for CR3022 among all other variants. These findings suggest that the newly emerged double mutant could significantly reduce the impact of the current vaccine which threatens the protective efficacy of current vaccine therapy.

    Discovery and in-vitro evaluation of potent SARS-CoV-2 entry inhibitors

    Authors: Arpan Acharya; Kabita Pandey; Michellie Thurman; Elizabeth Klug; Jay Trivedi; Christian L Lorson; Kamlendra Singh; Siddappa N Byrareddy

    doi:10.1101/2021.04.02.438204 Date: 2021-04-02 Source: bioRxiv

    SARS-CoV-2 infection MESHD initiates with the attachment of spike protein PROTEIN to the ACE2 HGNC receptor. While vaccines have been developed, no SARS-CoV-2 specific small molecule inhibitors have been approved. Herein, utilizing the crystal structure of the ACE2 HGNC/Spike receptor binding domain (S-RBD) complex in computer-aided drug design (CADD) approach, we docked ~8 million compounds within the pockets residing at S-RBD/ ACE2 HGNC interface. Five best hits depending on the docking score, were selected and tested for their in vitro efficacy to block SARS-CoV-2 replication. Of these, two compounds (MU-UNMC-1 and MU-UNMC-2) blocked SARS-CoV-2 replication at sub-micromolar IC50 in human bronchial epithelial cells (UNCN1T) and Vero cells. Furthermore, MU-UNMC-2 was highly potent in blocking the virus entry by using pseudoviral particles expressing SARS-CoV-2 spike PROTEIN. Finally, we found that MU-UNMC-2 is highly synergistic with remdesivir (RDV), suggesting that minimal amounts are needed when used in combination with RDV, and has the potential to develop as a potential entry inhibitor for COVID-19 MESHD.

    Qualitatively distinct modes of Sputnik V vaccine-neutralization escape by SARS-CoV-2 Spike PROTEIN variants

    Authors: Satoshi Ikegame; Mohammed N. A. Siddiquey; Chuan-Tien Hung; Griffin Haas; Luca Brambilla; Kasopefoluwa Y. Oguntuyo; Shreyas Kowdle; Ariel Esteban Vilardo; Alexis Edelstein; Claudia Perandones; Jeremy P. Kamil; Benhur Lee

    doi:10.1101/2021.03.31.21254660 Date: 2021-04-02 Source: medRxiv

    The novel pandemic betacoronavirus, severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), has infected at least 120 million people since its identification as the cause of a December 2019 viral pneumonia MESHD outbreak in Wuhan, China. Despite the unprecedented pace of vaccine development, with six vaccines already in use worldwide, the emergence of SARS-CoV-2 variants of concern (VOC) across diverse geographic locales suggests herd immunity may fail to eliminate the virus. All three officially designated VOC carry Spike (S) polymorphisms thought to enable escape from neutralizing antibodies elicited during initial waves of the pandemic. Here, we characterize the biological consequences of the ensemble of S mutations present in VOC lineages B.1.1.7 (501Y.V1) and B.1.351 (501Y.V2). Using a replication-competent EGFP-reporter vesicular stomatitis virus MESHD ( VSV MESHD) system, rcVSV-CoV2-S, which encodes S from SARS coronavirus 2 in place of VSV MESHD-G, coupled with a clonal HEK-293T ACE2 HGNC TMPRSS2 cell line optimized for highly efficient S-mediated infection, we determined that 8 out of 12 (75%) of serum samples from 12 recipients of the Russian Sputnik V Ad26 / Ad5 vaccine showed dose response curve slopes indicative of failure to neutralize rcVSV-CoV2-S: B.1.351. The same set of sera efficiently neutralized S from B.1.1.7 and showed only moderately reduced activity against S carrying the E484K substitution alone. Taken together, our data suggest that control of emergent SARS-CoV-2 variants may benefit from updated vaccines.

    Placental expression of ACE2 HGNC and TMPRSS2 HGNC in maternal SARS-CoV-2 infection MESHD: are placental defenses mediated by fetal sex?

    Authors: Lydia L Shook; Evan A Bordt; Marie-Charlotte Meinsohn; David Pepin; Rose M De Guzman; Sara Brigada; Laura J Yockey; Kaitlyn E James; Mackenzie W Sullivan; Lisa M Bebell; Drucilla J Roberts; Anjali J Kaimal; Danny Schust; Andrea G Edlow

    doi:10.1101/2021.04.01.438089 Date: 2021-04-01 Source: bioRxiv

    Background: Sex differences in vulnerability to and severity of SARS-CoV-2 infection MESHD have been described in non-pregnant populations. ACE2 HGNC and TMPRSS2 HGNC, host molecules required for viral entry, are regulated by sex steroids and expressed in the placenta. We sought to investigate whether placental ACE2 HGNC and TMPRSS2 HGNC expression vary by fetal sex and in the presence of maternal SARS-CoV-2 infection MESHD. Methods: Placental ACE2 HGNC and TMPRSS2 HGNC were quantified in 68 pregnant individuals (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. Maternal SARS-CoV-2 status was determined by nasopharyngeal RT-PCR. Placental SARS-CoV-2 viral load was quantified. RTqPCR was performed to quantify expression of ACE2 HGNC and TMPRSS2 HGNC relative to the reference gene YWHAZ HGNC. Western blots were performed on placental homogenates to quantify protein levels. The impact of fetal sex and SARS-CoV-2 exposure on ACE2 HGNC and TMPRSS2 HGNC expression was analyzed by 2-way ANOVA. Results: SARS-CoV-2 virus was undetectable in all placentas. Maternal SARS-CoV-2 infection MESHD impacted TMPRSS2 HGNC placental gene and protein expression in a sexually dimorphic fashion (2-way ANOVA interaction p-value: 0.002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on placental ACE2 HGNC gene or protein expression. Placental TMPRSS2 HGNC expression was significantly correlated with ACE2 HGNC expression in males (Spearman's rho=0.54, p=0.02) but not females (rho=0.23, p=0.34) exposed to maternal SARS-CoV-2. Conclusions: Sex differences in placental TMPRSS2 HGNC but not ACE2 HGNC were observed in the setting of maternal SARS-CoV-2 infection MESHD. These findings may have implications for offspring vulnerability to placental infection and vertical transmission.These findings may have implications for offspring vulnerability to placental infection and vertical transmission.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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