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      Virus-Like Particles of SARS-CoV-2 as Virus Surrogates: Morphology, Immunogenicity, and Internalization in Neuronal Cells

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          Abstract

          The engineering of virus-like particles (VLPs) is a viable strategy for the development of vaccines and for the identification of therapeutic targets without using live viruses. Here, we report the generation and characterization of quadruple-antigen SARS-CoV-2 VLPs. VLPs were generated by transient transfection of two expression cassettes in adherent HEK293T cells—one cassette containing M pro for processing of three structural proteins (M, E, and N), and the second cassette expressing the Spike protein. Further characterization revealed that the VLPs retain close morphological and antigenic similarity with the native virus and also bind strongly to the SARS-CoV-2 receptor hACE-2 in an in vitro binding assay. Interestingly, the VLPs were found to internalize into U87-MG cells through cholesterol-rich domains in a dynamin-dependent process. Finally, our results showed that mice immunized with VLPs induce robust humoral and cellular immune responses mediated by enhanced levels of IL-4, IL-17, and IFNγ. Taken together, our results demonstrate that VLPs mimic the native virus and induce a strong immune response, indicating the possible use of these particles as an alternative vaccine candidate against SARS-CoV-2. VLPs can also be effective in mapping the initial stages of virus entry and screening inhibitors.

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          Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

          Alexandra C Walls, Young-Jun Park, M. Alejandra Tortorici … (2020)
          Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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            Remdesivir for the Treatment of Covid-19 — Final Report

            John H. Beigel, Kay Tomashek, Lori Dodd … (2022)
            Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)
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              Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

              Jun Lan, Jiwan Ge, Jinfang Yu … (2020)
              A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world1-3. Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1-3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.
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                Author and article information

                Journal
                Journal ID (nlm-ta): ACS Infect Dis
                Journal ID (iso-abbrev): ACS Infect Dis
                Journal ID (publisher-id): id
                Journal ID (coden): aidcbc
                Title: ACS Infectious Diseases
                Publisher: American Chemical Society
                ISSN (Electronic): 2373-8227
                Publication date (Electronic): 21 September 2022
                Electronic Location Identifier: acsinfecdis.2c00217
                Affiliations
                [† ]Kusuma School of Biological Sciences, Indian Institute of Technology Delhi , Hauz Khas, New Delhi110016, India
                [‡ ]Translational Health Science and Technology Institute (THSTI) , NCR Biotech Science Cluster 3rd Milestone, Faridabad - Gurgaon Rd, Expressway, Faridabad, Haryana121001, India
                [§ ]Immunobiology/Immunology Core Laboratory, Translational Health Science and Technology Institute (THSTI) , NCR Biotech Science Cluster 3rd Milestone, Faridabad - Gurgaon Rd, Expressway, Faridabad, Haryana121001, India
                Author notes
                Author information
                https://orcid.org/0000-0001-6202-5965
                Article
                DOI: 10.1021/acsinfecdis.2c00217
                PMC ID: 9514328
                PubMed ID: 36129193
                SO-VID: 9dba49d8-5f35-4cc4-ae75-10c189d485b2
                Copyright © © 2022 American Chemical Society
                License:

                This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 23 April 2022
                Categories
                Subject: Article
                Custom metadata
                document-id-old-9 id2c00217
                document-id-new-14 id2c00217
                ccc-price

                Keywords: sars-cov-2,virus-like particles,morphology,antigenicity,u87-mg cells
                Data availability:
                Keywords: sars-cov-2, virus-like particles, morphology, antigenicity, u87-mg cells

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