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      Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells

      research-article
      , *
      Virology
      Elsevier Inc.
      Coronavirus, SARS, Spike protein, Virus entry, Endosomes, Calcium, Fusion peptide

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          Abstract

          During viral entry, enveloped viruses require the fusion of their lipid envelope with host cell membranes. For coronaviruses, this critical step is governed by the virally-encoded spike (S) protein, a class I viral fusion protein that has several unique features. Coronavirus entry is unusual in that it is often biphasic in nature, and can occur at or near the cell surface or in late endosomes. Recent advances in structural, biochemical and molecular biology of the coronavirus S protein has shed light on the intricacies of coronavirus entry, in particular the molecular triggers of coronavirus S-mediated membrane fusion. Furthermore, characterization of the coronavirus fusion peptide (FP), the segment of the fusion protein that inserts to a target lipid bilayer during membrane fusion, has revealed its particular attributes which imparts some of the unusual properties of the S protein, such as Ca 2+-dependency. These unusual characteristics can explain at least in part the biphasic nature of coronavirus entry. In this review, using severe acute respiratory syndrome coronavirus (SARS-CoV) as model virus, we give an overview of advances in research on the coronavirus fusion peptide with an emphasis on its role and properties within the biological context of host cell entry.

          Highlights

          • SARS-CoV as model for studying the coronavirus (CoV) fusion peptide (FP).

          • Evidence based on functional and biophysical analyses that reveal the region downstream of the coronavirus spike protein S2′ cleavage as the bona fide FP that forms an extended “fusion platform”.

          • Evidence for a direct role for calcium cations in mediating membrane fusion of SARS-CoV.

          • Unusual features of the CoV FP that set it apart from other class I fusion peptides.

          • The biphasic nature of SARS-CoV cellular entry pathways can be explained by calcium-dependency of fusion.

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          Most cited references41

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          Is Open Access

          Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein

          Coronaviruses are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. To deliver their nucleocapsid into the host cell, they rely on the fusion of their envelope with the host cell membrane. The spike glycoprotein (S) mediates virus entry and is a primary determinant of cell tropism and pathogenesis. It is classified as a class I fusion protein, and is responsible for binding to the receptor on the host cell as well as mediating the fusion of host and viral membranes—A process driven by major conformational changes of the S protein. This review discusses coronavirus entry mechanisms focusing on the different triggers used by coronaviruses to initiate the conformational change of the S protein: receptor binding, low pH exposure and proteolytic activation. We also highlight commonalities between coronavirus S proteins and other class I viral fusion proteins, as well as distinctive features that confer distinct tropism, pathogenicity and host interspecies transmission characteristics to coronaviruses.
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            A decade after SARS: strategies for controlling emerging coronaviruses

            Key Points Two highly pathogenic human coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), have emerged in the past decade. The lack of any clinically approved antiviral treatments or vaccines for either virus emphasizes the importance of the design of effective therapeutics and preventives. Bats have been implicated as reservoirs of both SARS-CoV and MERS-CoV as well as related viruses and other human coronaviruses (HCoVs), such as HCoV-229E and HCoV-NL63. The dispersion of bat species over much of the globe probably enhances their potential to act as reservoirs for pathogens, some of which are extremely virulent and potentially lethal to other animals and humans. Multiple animal models for SARS-CoV infection exist, although mouse models have been the most thoroughly characterized. Mouse-adapted SARS-CoV is capable of causing pathology that is representative of human infections in both young and aged animals. Small animal models for MERS-CoV infection have not yet been reported, although the possibility of further ongoing selection in the receptor-binding sequence in the spike protein or other sequences that are important for host specificity might contribute to this limitation. A mild disease phenotype that can include either localized or widespread pneumonia is observed in inoculated macaques. Multiple vaccine strategies have been attempted with coronaviruses, mostly (but not exclusively) targeting the spike glycoprotein. Successful live-attenuated vaccines have utilized reverse genetic strategies to delete the envelope protein or inactivate the exonuclease activity of non-structural protein 14 (nsp14) . MERS-CoV, similarly to SARS-CoV in 2003, has the potential to have a profound impact on the human population; however, its low penetrance thus far suggests that the virus might either ultimately fail to develop a niche in humans or it might still be adapting to human hosts and that the worst of its effects are yet to come. Coronavirus phylogeny shows an incredible diversity in antigenic variants, which leads to limited cross-protection against infection with different strains, even within a phylogenetic subcluster. Consequently, the risk of introducing novel coronaviruses into naive human and animal populations remains high. Supplementary information The online version of this article (doi:10.1038/nrmicro3143) contains supplementary material, which is available to authorized users.
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              Virus Entry: Open Sesame

              Detailed information about the replication cycle of viruses and their interactions with host organisms is required to develop strategies to stop them. Cell biology studies, live-cell imaging, and systems biology have started to illuminate the multiple and subtly different pathways that animal viruses use to enter host cells. These insights are revolutionizing our understanding of endocytosis and the movement of vesicles within cells. In addition, such insights reveal new targets for attacking viruses before they can usurp the host-cell machinery for replication.
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                Author and article information

                Contributors
                Journal
                Virology
                Virology
                Virology
                Elsevier Inc.
                0042-6822
                1096-0341
                21 December 2017
                April 2018
                21 December 2017
                : 517
                : 3-8
                Affiliations
                [0005]Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States
                Author notes
                [* ]Correspondence to: Department of Microbiology & Immunology, C4-127 VMC, Cornell University, Ithaca, NY 14853, United States. gary.whittaker@ 123456cornell.edu
                Article
                S0042-6822(17)30420-8
                10.1016/j.virol.2017.12.015
                7112017
                29275820
                b0e69ddb-2a53-4087-a9c1-e404544af79d
                © 2017 Elsevier Inc.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights 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 free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 31 October 2017
                : 13 December 2017
                : 15 December 2017
                Categories
                Article

                Microbiology & Virology
                coronavirus,sars,spike protein,virus entry,endosomes,calcium,fusion peptide
                Microbiology & Virology
                coronavirus, sars, spike protein, virus entry, endosomes, calcium, fusion peptide

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