Corpus overview


Overview

MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinS (100)

NSP5 (7)

ProteinN (4)

ComplexRdRp (4)

ProteinE (2)


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SARS-CoV-2 Proteins
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    Dynamic Interactions of Fully Glycosylated SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN Protein with Various Antibodies

    Authors: Yiwei Cao; Yeol Kyo Choi; Martin Frank; Hyeonuk Woo; Sang-Jun Park; Min Sun Yeom; Chaok Seok; Wonpil Im

    doi:10.1101/2021.05.10.443519 Date: 2021-05-11 Source: bioRxiv

    The spread of severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein PROTEIN on the viral envelope mediates human angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein PROTEIN models described in our previous work, and performed all-atom molecular dynamics simulations to get insight into the structural dynamics and interactions between S protein PROTEIN and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes, and the influences of antibody on the motion of S protein PROTEIN receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.

    SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity MESHD

    Authors:

    doi:10.1101/2021.05.09.443331 Date: 2021-05-10 Source: bioRxiv

    The need for SARS-CoV-2 next-generation vaccines has been highlighted by the rise of variants of concern (VoC) and the long-term threat of other coronaviruses. Here, we designed and characterized four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of prefusion Spike (S), S1 and RBD HGNC. These immunogens induced robust S-binding, ACE2-inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2 in mice. A Spike-ferritin nanoparticle (SpFN) vaccine elicited neutralizing titers more than 20-fold higher than convalescent donor serum, following a single immunization, while RBD-Ferritin nanoparticle ( RFN MESHD) immunogens elicited similar responses after two immunizations. Passive transfer of IgG purified from SpFN- or RFN-immunized mice protected K18- hACE2 HGNC transgenic mice from a lethal SARS-CoV-2 virus challenge. Furthermore, SpFN- and RFN-immunization elicited ACE2 blocking activity and neutralizing ID50 antibody titers >2,000 against SARS-CoV-1, along with high magnitude neutralizing titers against major VoC. These results provide design strategies for pan-coronavirus vaccine development.

    The Effect of Minnelide against SARS-CoV-2 in a Murine Model

    Authors:

    doi:10.1101/2021.05.05.442875 Date: 2021-05-06 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD, SARS-CoV-2, is the causative agent of coronavirus disease 2019 MESHD, COVID-19 MESHD, and the current COVID-19 pandemic MESHD. Even as more vaccine candidates are released, more treatment options are critically needed. Here, we investigated the use of Minnelide, a water soluble pro-drug with anti-inflammatory properties, for the treatment of COVID-19 MESHD. To do this, k18- hACE2 HGNC mice were infected with SARS-CoV-2 or given PBS control intranasally. The next day mice were either treated daily with low dose (0.0025mg/day) or high dose Minnelide (0.005mg/day), or given vehicle control intraperitoneal. Mice were weighed daily, and sacrificed at day 6 and 10 post-infection to analyze viral burden, cytokine response, and pathology. We observed a reduction in viral load in the lungs of Minnelide-treated mice infected with SARS-CoV-2 at day 10 post-infection compared to day 6 post-infection. All SARS-CoV-2 infected MESHD non-treated mice were moribund six days post-infection while treatment with Minnelide extended survival for both low (60% survival) and high (100% survival) dose treated mice ten days post-infection. Interestingly, cytokine analysis demonstrated a significant reduction in IL-6 (lung and heart) and D-dimer (serum) in high dose treated SARS-CoV-2 infected MESHD mice compared to mice infected with SARS-CoV-2 alone at day 6 post-infection. Additionally, histology analysis revealed that Minnelide treatment significantly improved lung pathology ten days post-infection with SARS-CoV-2 with all the mice exhibiting normal lung tissue with thin alveolar septa MESHD and no inflammatory cells. Overall, our study exhibits potential for the use of Minnelide to improve survival in COVID-19 MESHD patients.

    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.

    Mild and severe SARS-CoV-2 infection MESHD induces respiratory and intestinal microbiome changes in the K18- hACE2 HGNC transgenic mouse model

    Authors: Brittany A Seibert; Joaquin Caceres; Stivalis Cardenas-Garcia; Silvia Carnaccini; Ginger Geiger; Daniela Rajão; Elizabeth A Ottesen; Daniel R. Perez

    doi:10.1101/2021.04.20.440722 Date: 2021-04-23 Source: bioRxiv

    Transmission of the severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2), has resulted in millions of deaths MESHD and declining economies around the world. K18- hACE2 HGNC mice develop disease resembling severe SARS-CoV-2 infection MESHD in a virus dose-dependent manner. The relationship between SARS-CoV-2 and the intestinal or respiratory microbiome is not fully understood. In this context, we characterized the cecal and lung microbiome of SARS-CoV-2 challenged K18- hACE2 HGNC transgenic mice in the presence or absence of treatment with the Mpro PROTEIN inhibitor GC376. Cecum microbiome showed decreased Shannon and Inv Simpson diversity index correlating with SARS-CoV-2 infection MESHD dosage and a difference of Bray-Curtis MESHD dissimilarity distances among control and infected mice. Bacterial phyla such as Firmicutes, particularly Lachnospiraceae and Oscillospiraceae, were significantly less abundant while Verrucomicrobiota, particularly the family Akkermansiaceae, were increasingly more prevalent during peak infection in mice challenged with a high virus dose. In contrast to the cecal microbiome, the lung microbiome showed similar microbial diversity among the control, low and high challenge virus groups, independent of antiviral treatment. Bacterial phyla in the lungs such as Bacteroidota decreased while Firmicutes and Proteobacteria were significantly enriched in mice challenged with a high dose of SARS-CoV-2. In summary, we identified changes in the cecal and lung microbiome of K18- hACE2 HGNC mice with severe clinical signs of SARS-CoV-2 infection MESHD.

    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.

    Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection MESHD

    Authors: Martina Severa; Roberta Antonina Diotti; Marilena Paola Etna; Fabiana Rizzo; Stefano Fiore; Daniela Ricci; Marco Iannetta; Alessandro Sinigaglia; Alessandra Lodi; Nicasio Mancini; Elena Criscuolo; Massimo Clementi; Massimo Andreoni; Stefano Balducci; Luisa Barzon; Paola Stefanelli; Nicola Clementi; Eliana Coccia

    doi:10.1101/2021.04.17.440278 Date: 2021-04-19 Source: bioRxiv

    SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 MESHD ( COVID-19 MESHD) progression. Indeed, critically ill MESHD patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure MESHD. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7 HGNC/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19 MESHD. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2 HGNC-indipendent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 HGNC marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected MESHD subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 MESHD display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 MESHD patients.

    Antibody Cocktail Exhibits Broad Neutralization against SARS-CoV-2 and SARS-CoV-2 variants

    Authors: Yuanyuan Qu; Xueyan Zhang; Meiyu Wang; Lina Sun; Yongzhong Jiang; Cheng Li; Wei Wu; Zhen Chen; Qiangling Yin; Xiaolin Jiang; Yang Liu; Chuan Li; Jiandong Li; Tianlei Ying; Dexin Li; Faxian Zhan; Youchun Wang; Wuxiang Guan; Shiwen Wang; Mifang Liang

    doi:10.1101/2021.04.16.440083 Date: 2021-04-17 Source: bioRxiv

    Severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) has precipitated multiple variants resistant to therapeutic antibodies. In this study, 12 high-affinity antibodies were generated from convalescent donors in early outbreaks using immune antibody phage display libraries. Of them, two RBD-binding antibodies (F61 and H121) showed high affinity neutralization against SARS-CoV-2, whereas three S2-target antibodies failed to neutralize SARS-CoV-2. Following structure analysis, F61 identified a linear epitope located in residues G446 - S494, which overlapped with angiotensin-converting enzyme 2 HGNC ( ACE2 HGNC) binding sites, while H121 recognized a conformational epitope located on the side face of RBD, outside from ACE2 HGNC binding domain. Hence the cocktail of the two antibodies achieved better performance of neutralization to SARS-CoV-2. Importantly, F61 and H121 exhibited efficient neutralizing activity against variants B.1.1.7 and B.1.351, those showed immune escape. Efficient neutralization of F61 and H121 against multiple mutations within RBD revealed a broad neutralizing activity against SARS-CoV-2 variants, which mitigated the risk of viral escape. Our findings defined the basis of therapeutic cocktails of F61 and H121 with broad neutralization and delivered a guideline for the current and future vaccine design, therapeutic antibody development, and antigen diagnosis of SARS-CoV-2 and its novel 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.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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