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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.

    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.

    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.

    Genome-wide CRISPR activation screen identifies novel receptors for SARS-CoV-2 entry MESHD

    Authors: Shiyou Zhu; Ying Liu; Zhuo Zhou; Zhiying Zhang; Xia Xiao; Zhiheng Liu; Ang Chen; Xiaojing Dong; Feng Tian; Shihua Chen; Yiyuan Xu; Chunhui Wang; Qiheng Li; Xuran Niu; Qian Pan; Shuo Du; Junyu Xiao; Jianwei Wang; Wensheng Wei

    doi:10.1101/2021.04.08.438924 Date: 2021-04-09 Source: bioRxiv

    The ongoing pandemic of coronavirus disease 2019 MESHD ( COVID-19 MESHD) caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) has been endangering worldwide public health and economy. SARS-CoV-2 infects MESHD a variety of tissues where the known receptor ACE2 HGNC is low or almost absent, suggesting the existence of alternative pathways for virus entry. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection MESHD. In addition to known host proteins, i.e PROTEIN. ACE2 HGNC, TMPRSS2 HGNC, and NRP1 HGNC, we identified multiple host components, among which LDLRAD3 HGNC, TMEM30A HGNC, and CLEC4G HGNC were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spike's N-terminal domain ( NTD HGNC). Their essential and physiological roles have all been confirmed in either neuron or liver cells. In particular, LDLRAD3 HGNC and CLEC4G HGNC mediate SARS-CoV-2 entry MESHD and infection in a fashion independent of ACE2 HGNC. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of the therapeutic countermeasures against COVID-19 MESHD.

    Sulforaphane exhibits in vitro and in vivo antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses MESHD

    Authors: Alvaro A Ordonez; Cynthia K Bullen; Andres F Villabona-Rueda; Elizabeth A Thompson; Mitchell L Turner; Stephanie L Davis; Oliver Komm; Jonathan D Powell; Robert H Yolken; Sanjay K Jain; Lorraine Jones-Brando

    doi:10.1101/2021.03.25.437060 Date: 2021-03-25 Source: bioRxiv

    Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 MESHD ( COVID-19 MESHD), has incited a global health crisis. Currently, there are no orally available medications for prophylaxis for those exposed to SARS-CoV-2 and limited therapeutic options for those who develop COVID-19 MESHD. We evaluated the antiviral activity of sulforaphane ( SFN HGNC), a naturally occurring, orally available, well-tolerated, nutritional supplement present in high concentrations in cruciferous vegetables with limited side effects. SFN inhibited in vitro replication of four strains of SARS-CoV-2 as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection MESHD in vitro. Prophylactic administration of SFN to K18- hACE2 HGNC mice prior to intranasal SARS-CoV-2 infection MESHD significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury MESHD and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN is a promising treatment for prevention of coronavirus infection MESHD or treatment of early disease.

    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.

    Circadian regulation of SARS-CoV-2 infection MESHD in lung epithelial cells

    Authors: Xiaodong Zhuang; Senko Tsukuda; Florian Wrensch; Peter AC Wing; Helene Borrmann; James M Harris; Sophie B Morgan; Laurent Mailly; Nazia Thakur; Carina Conceicao; Harshmeena Sanghani; Laura Heydmann; Charlotte Bach; Anna Ashton; Steven Walsh; Tiong Kit Tan; Lisa Schimanski; Kuan-Ying A Huang; Catherine Schuster; Koichi Watashi; Timothy SC Hinks; Aarti Jagannath; Sridhar R Vausdevan; Dalan Bailey; Thomas F Baumert; Jane A McKeating

    doi:10.1101/2021.03.20.436163 Date: 2021-03-21 Source: bioRxiv

    The COVID-19 pandemic MESHD, caused by SARS-CoV-2 coronavirus MESHD, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract, via binding human angiotensin-converting enzyme ( ACE2 HGNC), and infection can result in pneumonia MESHD and acute respiratory distress syndrome MESHD. Circadian rhythms coordinate an organisms response to its environment and recent studies report a role for the circadian clock to regulate host susceptibility to virus infection MESHD. Influenza A infection of arhythmic mice, lacking the circadian component BMAL1, results in higher viral replication and elevated inflammatory responses leading to more severe bronchitis MESHD, highlighting the impact of circadian pathways in respiratory function. We demonstrate circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with the synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry MESHD and RNA replication. Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Our study suggests new approaches to understand and improve therapeutic targeting of COVID-19 MESHD.

    SARS-CoV-2 Viremia MESHD is Associated with Distinct Proteomic Pathways and Predicts COVID-19 MESHD Outcomes

    Authors: Yijia Li; Alexis M Schneider; Arnav Mehta; Moshe Sade-Feldman; Kyle R Kays; Matteo Gentili; Nicole C Charland; Anna LK Gonye; Irena Gushterova; Hargun K Khanna; Thomas J LaSalle; Kendall M Lavin-Parsons; Brendan M Lilley; Carl L Lodenstein; Kasidet Manakongtreecheep; Justin D Margolin; Brenna N McKaig; Blair A Parry; Maricarmen Rojas-Lopez; Brian C Russo; Nihaarika Sharma; Jessica Tantivit; Molly F Thomas; James Regan; James P Flynn; Alexandra-Chloe Villani; Nir Hacohen; Marcia B Goldberg; Michael R Filbin; Jonathan Z Li

    doi:10.1101/2021.02.24.21252357 Date: 2021-02-26 Source: medRxiv

    Background: Severe Acute Respiratory Syndrome Coronavirus 2 MESHD (SARS-CoV-2) plasma viremia MESHD has been associated with severe disease and death in coronavirus disease MESHD coronavirus disease 2019 MESHD ( COVID-19 MESHD) in small-scale cohort studies. The mechanisms behind this association remain elusive. Methods: We evaluated the relationship between SARS-CoV-2 viremia MESHD, disease outcome, inflammatory and proteomic profiles in a cohort of COVID-19 MESHD emergency department participants. SARS-CoV-2 viral load was measured using qRT-PCR based platform. Proteomic data were generated with Proximity Extension Assay (PEA) using the Olink platform. Results: Three hundred participants with nucleic acid test-confirmed COVID-19 MESHD were included in this study. Levels of plasma SARS-CoV-2 viremia MESHD at the time of presentation predicted adverse disease outcomes, with an adjusted odds ratio (aOR) of 10.6 (95% confidence interval [CI] 4.4, 25.5, P<0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and aOR of 3.9 (95%CI 1.5, 10.1, P=0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia MESHD, including upregulation of SARS-CoV-2 entry factors ( ACE2 HGNC, CTSL HGNC, FURIN HGNC), heightened markers of tissue damage to the lungs, gastrointestinal tract, endothelium/vasculature and alterations in coagulation pathways. Conclusions: These results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia MESHD that underlies its ability to predict COVID-19 MESHD disease outcomes.

    Comprehensive evaluation of ACE2 HGNC expression in female ovary by single-cell RNA-seq analysis

    Authors: Siming Kong; Zhiqiang Yan; Peng Yuan; Xixi Liu; Yidong Chen; Ming Yang; Wei Chen; Shi Song; Jie Yan; Liying Yan; Jie Qiao

    doi:10.1101/2021.02.23.432460 Date: 2021-02-23 Source: bioRxiv

    Pneumonia induced by severe acute respiratory coronavirus MESHD 2 (SARS-CoV-2) via ACE2 HGNC receptor may affect many organ systems like lung, heart and kidney. An autopsy report revealed positive SARS-Cov-2 detection results in ovary MESHD, however, the developmental-stage-specific and cell-type-specific risk in fetal primordial germ cells (PGCs) and adult women ovary remained unclear. In this study, we used single-cell RNA-sequencing (scRNA-seq) datasets spanning several developmental stages of ovary MESHD including PGCs and cumulus-oocyte complex (COC) to investigate the potential risk of SARS-CoV-2 infection MESHD. We found that PGCs and COC exhibited high ACE2 HGNC expression. More importantly, the ratio of ACE2 HGNC-positive cells was sharply up-regulated in primary stage and ACE2 HGNC was expressed in all oocytes and cumulus cells in preovulatory stage, suggesting the possible risk of SARS-CoV-2 infection MESHD in follicular development. CatB HGNC/L, not TMPRSS2 HGNC, was identified to prime for SARS-CoV-2 entry MESHD in follicle. Our findings provided insights into the potential risk of SARS-CoV-2 infection MESHD during folliculogenesis in adulthood and the possible risk in fetal PGCs.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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