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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (99)

NSP5 (4)

ComplexRdRp (2)

ProteinN (2)

ORF8 (1)


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    SARS-CoV-2 spike PROTEIN protein induces brain pericyte immunoreactivity in absence of productive viral infection

    Authors: Rayan Khaddaj-Mallat; Natija Aldib; Anne-Sophie Paquette; Aymeric Ferreira; Sarah Lecordier; Maxime Bernard; Armen Saghatelyan; Ayman ElAli

    doi:10.1101/2021.04.30.442194 Date: 2021-05-03 Source: bioRxiv

    COVID-19 MESHD is a respiratory disease MESHD caused by severe acute respiratory syndrome coronavirus-2 MESHD (SARS-CoV-2). COVID-19 MESHD pathogenesis causes vascular-mediated neurological disorders MESHD via still elusive mechanisms. SARS-CoV-2 infects host MESHD cells by binding to angiotensin-converting enzyme 2 HGNC (ACE2), a transmembrane receptor that recognizes the viral spike (S) protein PROTEIN. Brain pericytes were recently shown to express ACE2 at the neurovascular interface, outlining their possible implication in microvasculature injury MESHD in COVID-19 MESHD. Yet, pericyte responses to SARS-CoV-2 is still to be fully elucidated. Using cell-based assays, we report that ACE2 HGNC expression in human brain vascular pericytes is highly dynamic and is increased upon S protein PROTEIN stimulation. Pericytes exposed to S protein PROTEIN underwent profound phenotypic changes translated by increased expression of contractile and myofibrogenic proteins, namely -smooth muscle actin (- SMA HGNC), fibronectin HGNC, collagen I, and neurogenic locus notch homolog protein-3 HGNC ( NOTCH3 HGNC). These changes were associated to an altered intracellular calcium (Ca2+) dynamic. Furthermore, S protein PROTEIN induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B ( NF-{kappa}B HGNC) signalling pathway, which was potentiated by hypoxia MESHD, a condition associated to vascular comorbidities, which exacerbate COVID-19 MESHD pathogenesis. S protein PROTEIN exposure combined to hypoxia MESHD enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely interleukin-8 HGNC ( IL-8 HGNC), IL-18 HGNC, macrophage migration inhibitory factor HGNC ( MIF HGNC), and stromal cell-derived factor-1 HGNC ( SDF-1 HGNC). Finally, we found that S protein PROTEIN could reach the mouse brain via the intranasal route and that reactive ACE2-expressing pericytes are recruited to the damaged tissue undergoing fibrotic scarring in a mouse model of cerebral multifocal micro-occlusions, a main reported vascular-mediated neurological condition associated to COVID-19 MESHD. Our data demonstrate that the released S protein PROTEIN is sufficient to mediate pericyte immunoreactivity, which may contribute to microvasculature injury MESHD in absence of a productive viral infection MESHD. Our study provides a better understanding for the possible mechanisms underlying cerebrovascular disorders MESHD in COVID-19 MESHD, paving the way to develop new therapeutic interventions.

    Convergent evolution of SARS-CoV-2 spike PROTEIN mutations, L452R, E484Q and P681R, in the second wave of COVID-19 MESHD in Maharashtra, India

    Authors: Sarah Cherian; Varsha Potdar; Santosh Jadhav; Pragya Yadav; Nivedita Gupta; Mousmi Das; Soumitra Das; Anurag Agarwal; Sujeet Singh; Priya Abraham; Samiran Panda; Shekhar Mande; Renu Swarup; Balram Bhargava; Rajesh Bhushan; - NIC team; - INSACOG Consortium

    doi:10.1101/2021.04.22.440932 Date: 2021-04-24 Source: bioRxiv

    As the global severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) pandemic expands, genomic epidemiology and whole genome sequencing are being constantly used to investigate its transmissions and evolution. In the backdrop of the global emergence of variants of concern (VOCs) during December 2020 and an upsurge in a state in the western part of India since January 2021, whole genome sequencing and analysis of spike protein PROTEIN mutations using sequence and structural approaches was undertaken to identify possible new variants and gauge the fitness of current circulating strains. Phylogenetic analysis revealed that the predominant clade in circulation was a distinct newly identified lineage B.1.617 possessing common signature mutations D111D, G142D, L452R, E484Q, D614G and P681R, in the spike protein PROTEIN including within the receptor binding domain (RBD). Of these, the mutations at residue positions 452, 484 and 681 have been reported in other globally circulating lineages. The structural analysis of RBD mutations L452R and E484Q along with P681R in the furin cleavage site, may possibly result in increased ACE2 HGNC binding and rate of S1-S2 cleavage resulting in better transmissibility. The same two RBD mutations indicated decreased binding to selected monoclonal antibodies (mAbs) and may affect their neutralization potential. Experimental validation is warranted for accessing both ACE2 HGNC binding and the effectiveness of commonly elicited neutralizing mAbs for the strains of lineage B.1.617. The emergence of such local variants through the accumulation of convergent mutations during the COVID-19 MESHD second wave needs to be further investigated for their public health impact in the rest of the country and its possibility of becoming a VOC.

    Inferring the stabilization effects of SARS-CoV-2 variants on the binding with ACE2 HGNC receptor

    Authors: Mattia Miotto; Lorenzo Di Rienzo; Giorgio Gosti; Leonardo Bo; Giacomo Parisi; Roberta Piacentini; Alberto Boffi; Giancarlo Ruocco; Edoardo Milanetti

    doi:10.1101/2021.04.18.440345 Date: 2021-04-19 Source: bioRxiv

    With the progression of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2 MESHD) pandemic, several variants of the virus are emerging with mutations distributed all over the viral sequence. While most of them are expected to have little to no effects at the phenotype level, some of these variants presenting specific mutations on the Spike protein PROTEIN are rapidly spreading, making urgent the need of characterizing their effects on phenotype features like contagiousness and antigenicity. With this aim, we performed extensive molecular dynamics simulations on a selected set of possible Spike variants in order to assess the stabilizing effect of particular amino acid substitutions, with a special focus on the mutations that are both characteristic of the top three most worrying variants at the moment, i.e the English, South African and Amazonian ones, and that occur at the molecular interface between SARS-CoV-2 Spike PROTEIN SARS-CoV-2 Spike MESHD protein and its human ACE2 receptor. We characterize these variants' effect in terms of (i) residues mobility, (ii) compactness, studying the network of interactions at the interface, and (iii) variation of shape complementarity via expanding the molecular surfaces in the Zernike basis. Overall, our analyses highlighted greater stability of the three variant complexes with respect to both the wild type and two negative control systems, especially for the English and Amazonian variants. In addition, in the three variants, we investigate the effects a not-yet observed mutation in position 501 could provoke on complex stability. We found that a phenylalanine mutation behaves similarly to the English variant and may cooperate in further increasing the stability of the South African one, hinting at the need for careful surveillance for the emergence of such kind of mutations in the population. Ultimately, we show that the observables we propose describe key features for the stability of the ACE2 HGNC-spike complex and can help to monitor further possible spike variants.

    Structural basis for enhanced infectivity and immune evasion of SARS-CoV-2 variants

    Authors: Christy L. Lavine; Shaun Rawson; Haisun Zhu; Krishna Anand; Pei Tong; Avneesh Gautam; Shen Lu; Sarah Sterling; Richard M Walsh Jr.; Jianming Lu; Wei Yang; Michael S Seaman

    doi:10.1101/2021.04.13.439709 Date: 2021-04-14 Source: bioRxiv

    Several fast-spreading variants of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) have become the dominant circulating strains that continue to fuel the COVID-19 pandemic MESHD despite intensive vaccination efforts throughout the world. We report here cryo-EM structures of the full-length spike (S) trimers of the B.1.1.7 and B.1.351 variants, as well as their biochemical and antigenic properties. Mutations in the B.1.1.7 protein increase the accessibility of its receptor binding domain and also the binding affinity for receptor angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC). The enhanced receptor engagement can account for the increased transmissibility and risk of mortality as the variant may begin to infect efficiently infect MESHD additional cell types expressing low levels of ACE2 HGNC. The B.1.351 variant has evolved to reshape antigenic surfaces of the major neutralizing sites on the S protein PROTEIN, rendering complete resistance to some potent neutralizing antibodies. These findings provide structural details on how the wide spread of SARS-CoV-2 enables rapid evolution to enhance viral fitness MESHD and immune evasion. They may guide intervention strategies to control the pandemic.

    Epitope classification and RBD binding properties of neutralizing antibodies against SARS-CoV-2 variants of concern

    Authors: Ashlesha Deshpande; Bethany D. Harris; Luis Martinez-Sobrido; James J. Kobie; Mark R Walter

    doi:10.1101/2021.04.13.439681 Date: 2021-04-13 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus-2 MESHD (SAR-CoV-2) causes coronavirus disease 2019 MESHD ( COVID19 MESHD) that is responsible for short and long-term disease, as well as death, in susceptible hosts. The receptor binding domain (RBD) of the SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN ( S) protein PROTEIN binds to cell surface angiotensin converting enzyme type-II ( ACE2 HGNC) to initiate viral attachment and ultimately viral pathogenesis. The SARS-CoV-2 S RBD MESHD is a major target of neutralizing antibodies (NAbs) that block RBD - ACE2 HGNC interactions. In this report, NAb-RBD binding epitopes in the protein databank were classified as C1, C1D, C2, C3, or C4 HGNC, using a RBD binding profile (BP), based on NAb-specific RBD buried surface area and used to predict the binding epitopes of a series of uncharacterized NAbs. Naturally occurring SARS-CoV-2 RBD sequence variation was also quantified to predict NAb binding sensitivities to the RBD-variants. NAb and ACE2 HGNC binding studies confirmed the NAb classifications and determined whether the RBD variants enhanced ACE2 HGNC binding to promote viral infectivity, and/or disrupted NAb binding to evade the host immune response. Of 9 single RBD mutants evaluated, K417T, E484K, and N501Y disrupted binding of 65% of the NAbs evaluated, consistent with the assignment of the SARS-CoV-2 P.1 Japan/Brazil strain as a variant of concern (VoC). RBD variants E484K and N501Y exhibited ACE2 HGNC binding equivalent to a Wuhan-1 reference SARS-CoV-2 RBD. While slightly less disruptive to NAb binding, L452R enhanced ACE2 HGNC binding affinity. Thus, the L452R mutant, associated with the SARS-CoV-2 California VoC MESHD (B.1.427/B.1.429-California), has evolved to enhance ACE2 HGNC binding, while simultaneously disrupting C1 and C2 NAb classes. The analysis also identified a non-overlapping antibody pair (1213H7 and 1215D1) that bound to all SARS-CoV-2 RBD variants evaluated, representing an excellent therapeutic option for treatment of SARS-CoV-2 WT MESHD and VoC strains.

    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.

    A bispecific monomeric nanobody induces SARS-COV-2 spike trimer dimers

    Authors: Leo Hanke; Hrishikesh Das; Daniel Sheward; Laura Perez Vidakovics; Egon Urgard; Ainhoa Moliner Morro; Vivien Karl; Alec Pankow; Kim Changil; Natalie Smith; Gabriel Pedersen; Jonathan M Coquet; B Martin Hallberg; Benjamin Murrell; Gerald M McInerney

    doi:10.1101/2021.03.20.436243 Date: 2021-03-21 Source: bioRxiv

    Antibodies binding to the severe acute respiratory syndrome coronavirus 2 MESHD ( SARS-CoV-2) spike PROTEIN have therapeutic promise, but emerging variants show the potential for virus escape. Thus, there is a need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we isolated a nanobody that potently neutralizes SARS-CoV-2, including the B.1.351 variant, and cross-neutralizes SARS-CoV MESHD. We demonstrate the therapeutic potential of the nanobody in a human ACE2 HGNC transgenic mouse model. Using biochemistry and electron cryomicroscopy we show that this nanobody simultaneously interacts with two RBDs from different spike trimers, rapidly inducing the formation of spike trimer-dimers. This naturally elicited bispecific monomeric nanobody establishes a novel strategy for potent immobilization of viral antigens.

    Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection MESHD

    Authors: Zhuo Zhou; Xinyi Zhang; Xiaobo Lei; Xia Xiao; Tao Jiao; Ruiyi Ma; Xiaojing Dong; Qi Jiang; Wenjing Wang; Yujin Shi; Tian Zheng; Yuting Tan; Zichun Xiang; Lili Ren; Tao Deng; Zhengfan Jiang; Zhixun Dou; Wensheng Wei; Jianwei Wang

    doi:10.21203/rs.3.rs-235742/v1 Date: 2021-02-12 Source: ResearchSquare

    The global coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic is caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection MESHD remain to be determined. Here, we report that SARS-CoV-2 infection MESHD activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection MESHD induces the cellular level of 2'3'-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection MESHD. We further demonstrate that the expression of spike protein PROTEIN from SARS-CoV-2 and ACE2 HGNC from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS HGNC mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection MESHD, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19 MESHD. In addition, these findings extend our knowledge in host defense against viral infection MESHD by showing that host cells’ self-nucleic acids can be employed as a “danger signal” to alarm the immune system.

    Transformations, Comparisons, and Analysis of Down to Up Protomer States of Variants of the SARS-CoV-2 Prefusion Spike Protein PROTEIN Including the UK Variant B.1.1.7

    Authors: michael h peters; Oscar Basidas; Daniel Kokron; Christopher E. Henze

    doi:10.1101/2021.02.09.430519 Date: 2021-02-09 Source: bioRxiv

    Monitoring and strategic response to variants in SARS-CoV-2 represents a considerable challenge in the current pandemic, as well as potentially future viral outbreaks of similar magnitude. In particular mutations and deletions involving the virion's prefusion Spike protein PROTEIN has significant potential impact on vaccines and therapeutics that utilize this key structural viral protein in their mitigation strategies. In this study, we have demonstrated how dominant energetic landscape mappings ("glue points") coupled with sequence alignment information can potentially identify or flag key residue mutations and deletions associated with variants. Surprisingly, we also found excellent homology of stabilizing residue glue points across the lineage of $\beta$ coronavirus Spike proteins MESHD Spike proteins PROTEIN, and we have termed this as "sequence homologous glue points". In general, these flagged residue mutations and/or deletions are then computationally studied in detail using all-atom biocomputational molecular dynamics over approximately one microsecond in order to ascertain structural and energetic changes in the Spike protein PROTEIN associated variants. Specifically, we examined both a theoretically-based triple mutant and the so-called UK or B.1.1.7 variant. For the theoretical triple mutant, we demonstrated through Alanine mutations, which help "unglue" key residue-residue interactions, that these three key stabilizing residues could cause the transition of Down to Up protomer states, where the Up protomer state allows binding of the prefusion Spike protein PROTEIN to hACE2 HGNC host cell receptors, whereas the Down state is believed inaccessible. For the B.1.1.7 variant, we demonstrated the critical importance of D614G and N5017 on the structure and binding of the Spike protein PROTEIN associated variant. In particular, we had previously identified D614 as a key glue point in the inter-protomer stabilization of the Spike protein PROTEIN. Other mutations and deletions associated with this variant did not appear to play a pivotal role in structure or binding changes. The mutant D614G is a structure breaking Glycine mutation demonstrating a relatively large hinge angle and highly stable Up conformation in agreement with previous studies. In addition, we demonstrate that the mutation N501Y may significantly increase the Spike protein PROTEIN binding to hACE2 HGNC cell receptors through its interaction with Y41 of hACE2 HGNC forming a potentially strong hydrophobic residue binding pair. We note that these two key mutations, D614G and N501Y, are also found in the so-called South African (SA; B.1.351) variant of SARS-CoV-2. Future studies along these lines are therefore aimed at mapping glue points to residue mutations and deletions of associated prefusion Spike protein PROTEIN variants in order to help direct and optimize efforts aimed at the mitigation of this deadly virion.

    In silico, in vitro and in cellulo models for monitoring SARS-CoV-2 spike PROTEIN/human ACE2 HGNC complex, viral entry and cell fusion

    Authors:

    doi:10.1101/2021.02.03.429555 Date: 2021-02-03 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) is the etiologic agent responsible for the recent coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic. Productive SARS-CoV-2 infection MESHD relies on viral entry into cells expressing angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC). Indeed, viral entry into cells is mostly mediated by the early interaction between the viral spike protein S PROTEIN and its ACE2 HGNC receptor. The S/ ACE2 HGNC complex is, thus, the first contact point between the incoming virus and its cellular target; consequently, it has been considered an attractive therapeutic target. To further characterize this interaction and the cellular processes engaged in the entry step of the virus, we set up various in silico, in vitro and in cellulo approaches that allowed us to specifically monitor the S/ ACE2 HGNC association. We report here a novel computational model of the SARS-CoV-2 S/ ACE2 HGNC complex as well as its biochemical and biophysical monitoring using pulldown, AlphaLISA and biolayer interferometry (BLI) binding assays. This led us to determine the kinetic parameters of the S/ ACE2 HGNC association and dissociation steps. In parallel to these in vitro approaches, we developed in cellulo transduction assays using SARS-CoV-2 pseudotyped lentiviral vectors and HEK293T- ACE2 HGNC cell lines generated in-house. This allowed us to recapitulate the early replication stage of the infection mediated by the S/ ACE2 HGNC interaction and to detect cell fusion induced by the interaction. Finally, a cell imaging system was set up to directly monitor the S/ ACE2 HGNC interaction in a cellular context, and a flow cytometry assay was developed to quantify this association at the cell surface. Together, these different approaches are available for both basic and clinical research aiming to characterize the entry step of the original SARS-CoV-2 strain and its variants as well as to investigate the possible chemical modulation of this interaction. All these models will help in identifying new antiviral agents and new chemical tools for dissecting the virus entry step.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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