scholarly journals Distinct conformational states of SARS-CoV-2 spike protein

Science ◽  
2020 ◽  
pp. eabd4251 ◽  
Author(s):  
Yongfei Cai ◽  
Jun Zhang ◽  
Tianshu Xiao ◽  
Hanqin Peng ◽  
Sarah M. Sterling ◽  
...  
Keyword(s):  
Immune Responses ◽  
Fusion Peptide ◽  
Intervention Strategies ◽  
Spike Protein ◽  
Target Cells ◽  
Spontaneous Transition ◽  
S Protein ◽  
Host Immune Responses ◽  
Binding Domains ◽  
External Conditions

Intervention strategies are urgently needed to control the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic. The trimeric viral spike (S) protein catalyzes fusion between viral and target cell membranes to initiate infection. Here we report two cryo-EM structures, derived from a preparation of the full-length S protein, representing its prefusion (2.9Å resolution) and postfusion (3.0Å resolution) conformations, respectively. The spontaneous transition to the postfusion state is independent of target cells. The prefusion trimer has three receptor-binding domains clamped down by a segment adjacent to the fusion peptide. The postfusion structure is strategically decorated by N-linked glycans, suggesting possible protective roles against host immune responses and harsh external conditions. These findings advance our understanding of SARS-CoV-2 entry and may guide development of vaccines and therapeutics.

scholarly journals Distinct conformational states of SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Yongfei Cai ◽  
Jun Zhang ◽  
Tianshu Xiao ◽  
Hanqin Peng ◽  
Sarah M. Sterling ◽  
...  
Keyword(s):  
Immune Responses ◽  
Structural Transition ◽  
Intervention Strategies ◽  
Target Cells ◽  
S Protein ◽  
Host Immune Responses ◽  
Mild Conditions ◽  
Binding Domains ◽  
External Conditions ◽  
Packed Structure

AbstractThe ongoing SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic has created urgent needs for intervention strategies to control the crisis. The spike (S) protein of the virus forms a trimer and catalyzes fusion between viral and target cell membranes - the first key step of viral infection. Here we report two cryo-EM structures, both derived from a single preparation of the full-length S protein, representing the prefusion (3.1Å resolution) and postfusion (3.3Å resolution) conformations, respectively. The spontaneous structural transition to the postfusion state under mild conditions is independent of target cells. The prefusion trimer forms a tightly packed structure with three receptor-binding domains clamped down by a segment adjacent to the fusion peptide, significantly different from recently published structures of a stabilized S ectodomain trimer. The postfusion conformation is a rigid tower-like trimer, but decorated by N-linked glycans along its long axis with almost even spacing, suggesting possible involvement in a mechanism protecting the virus from host immune responses and harsh external conditions. These findings advance our understanding of how SARS-CoV-2 enters a host cell and may guide development of vaccines and therapeutics.

scholarly journals Mutations in the Spike Protein of Middle East Respiratory Syndrome Coronavirus Transmitted in Korea Increase Resistance to Antibody-Mediated Neutralization

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Hannah Kleine-Weber ◽  
Mahmoud Tarek Elzayat ◽  
Lingshu Wang ◽  
Barney S. Graham ◽  
Marcel A. Müller ◽  
...  
Keyword(s):  
Middle East ◽  
Protein Binding ◽  
Receptor Binding ◽  
Viral Entry ◽  
Middle East Respiratory Syndrome ◽  
Spike Protein ◽  
Target Cells ◽  
S Protein ◽  
Hospital Outbreak ◽  
The Republic

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) poses a threat to public health. The virus is endemic in the Middle East but can be transmitted to other countries by travel activity. The introduction of MERS-CoV into the Republic of Korea by an infected traveler resulted in a hospital outbreak of MERS that entailed 186 cases and 38 deaths. The MERS-CoV spike (S) protein binds to the cellular protein DPP4 via its receptor binding domain (RBD) and mediates viral entry into target cells. During the MERS outbreak in Korea, emergence and spread of viral variants that harbored mutations in the RBD, D510G and I529T, was observed. Counterintuitively, these mutations were found to reduce DPP4 binding and viral entry into target cells. In this study, we investigated whether they also exerted proviral effects. We confirm that changes D510G and I529T reduce S protein binding to DPP4 but show that this reduction only translates into diminished viral entry when expression of DPP4 on target cells is low. Neither mutation modulated S protein binding to sialic acids, S protein activation by host cell proteases, or inhibition of S protein-driven entry by interferon-induced transmembrane proteins. In contrast, changes D510G and I529T increased resistance of S protein-driven entry to neutralization by monoclonal antibodies and sera from MERS patients. These findings indicate that MERS-CoV variants with reduced neutralization sensitivity were transmitted during the Korean outbreak and that the responsible mutations were compatible with robust infection of cells expressing high levels of DPP4. IMPORTANCE MERS-CoV has pandemic potential, and it is important to identify mutations in viral proteins that might augment viral spread. In the course of a large hospital outbreak of MERS in the Republic of Korea in 2015, the spread of a viral variant that contained mutations in the viral spike protein was observed. These mutations were found to reduce receptor binding and viral infectivity. However, it remained unclear whether they also exerted proviral effects. We demonstrate that these mutations reduce sensitivity to antibody-mediated neutralization and are compatible with robust infection of target cells expressing large amounts of the viral receptor DPP4.

scholarly journals Viral and Cellular Determinants of the Hepatitis C Virus Envelope-Heparan SulfateInteraction

2006 ◽  
Vol 80 (21) ◽  
pp. 10579-10590 ◽  
Author(s):  
Heidi Barth ◽  
Eva K. Schnober ◽  
Fuming Zhang ◽  
Robert J. Linhardt ◽  
Erik Depla ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Viral Infection ◽  
Viral Envelope ◽  
Model Systems ◽  
Target Cells ◽  
Virus Envelope ◽  
Viral Attachment ◽  
Host Immune Responses

ABSTRACT Cellular binding and entry of hepatitis C virus (HCV) are the first steps of viral infection and represent a major target for antiviral antibodies and novel therapeutic strategies. We have recently demonstrated that heparan sulfate (HS) plays a key role in the binding of HCV envelope glycoprotein E2 to target cells (Barth et al., J. Biol. Chem. 278:41003-41012, 2003). In this study, we characterized the HCV-HS interaction and analyzed its inhibition by antiviral host immune responses. Using recombinant envelope glycoproteins, virus-like particles, and HCV pseudoparticles as model systems for the early steps of viral infection, we mapped viral and cellular determinants of HCV-HS interaction. HCV-HS binding required a specific HS structure that included N-sulfo groups and a minimum of 10 to 14 saccharide subunits. HCV envelope binding to HS was mediated by four viral epitopes overlapping the E2 hypervariable region 1 and E2-CD81 binding domains. In functional studies using HCV pseudoparticles, we demonstrate that HCV binding and entry are specifically inhibited by highly sulfated HS. Finally, HCV-HS binding was markedly inhibited by antiviral antibodies derived from HCV-infected individuals. In conclusion, our results demonstrate that binding of the viral envelope to a specific HS configuration represents an important step for the initiation of viral infection and is a target of antiviral host immune responses in vivo. Mapping of viral and cellular determinants of HCV-HS interaction sets the stage for the development of novel HS-based antiviral strategies targeting viral attachment and entry.

scholarly journals CD8+ T cell epitope variations suggest a potential antigen presentation deficiency for spike protein of SARS-CoV-2

2021 ◽  
Author(s):  
Congling Qiu ◽  
Chanchan Xiao ◽  
Zhigang Wang ◽  
Xiongfei Chen ◽  
Lijuan Gao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Vaccine Development ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
Spike Protein ◽  
Target Cells

AbstractCOVID-19 is caused by a newly identified coronavirus, SARS-CoV-2, and has become a pandemic around the world. The illustration of the immune responses against SARS-CoV-2 is urgently needed for understanding the pathogenesis of the disease and its vaccine development. CD8+ T cells are critical for virus clearance and induce long lasting protection in the host. Here we identified specific HLA-A2 restricted T cell epitopes in the spike protein of SARS-CoV-2. Seven epitope peptides (n-Sp1, 2, 6, 7, 11, 13, 14) were confirmed to bind with HLA-A2 and potentially be presented by antigen presenting cells to induce host immune responses. Tetramers containing these peptides could interact with specific CD8+ T cells from convalescent COVID-19 patients, and one dominant epitope (n-Sp1) was defined. In addition, these epitopes could activate and generate epitope-specific T cells in vitro, and those activated T cells showed cytotoxicity to target cells. Meanwhile, all these epitopes exhibited high frequency of variations. Among them, n-Sp1 epitope variation 5L>F significantly decreased the proportion of specific T cell activation; n-Sp1 epitope 8L>V variant showed significantly reduced binding to HLA-A2 and decreased the proportion of n-Sp1-specific CD8+ T cell, which potentially contributes to the immune escape of SAR-CoV-2.

scholarly journals Antibody Responses to SARS-CoV-2 mRNA Vaccines Are Detectable in Saliva

2021 ◽  
Vol 6 (1) ◽  
pp. 116-134
Author(s):  
Thomas J. Ketas ◽  
Devidas Chaturbhuj ◽  
Victor M. Cruz Portillo ◽  
Erik Francomano ◽  
Encouse Golden ◽  
...  
Keyword(s):  
Immune Responses ◽  
Serum Antibody ◽  
Cross Sectional Study ◽  
Antibody Responses ◽  
Target Cells ◽  
Receptor Binding Domain ◽  
Sectional Study ◽  
Cross Sectional ◽  
S Protein ◽  
Iga Antibodies

The approved Pfizer and Moderna mRNA vaccines are well known to induce serum antibody responses to the SARS-CoV-2 Spike (S)-protein. However, their abilities to elicit mucosal immune responses have not been reported. Saliva antibodies represent mucosal responses that may be relevant to how mRNA vaccines prevent oral and nasal SARS-CoV-2 transmission. Here, we describe the outcome of a cross-sectional study on a healthcare worker cohort (WELCOME-NYPH), in which we assessed whether IgM, IgG, and IgA antibodies to the S-protein and its receptor-binding domain (RBD) were present in serum and saliva samples. Anti-S-protein IgG was detected in 14/31 and 66/66 of saliva samples from uninfected participants after vaccine doses-1 and -2, respectively. IgA antibodies to the S-protein were present in 40/66 saliva samples after dose 2. Anti-S-protein IgG was present in every serum sample from recipients of 2 vaccine doses. Vaccine-induced antibodies against the RBD were also frequently present in saliva and sera. These findings may help our understanding of whether and how vaccines may impede SARS-CoV-2 transmission, including to oral cavity target cells.

scholarly journals Japanese Encephalitis Virus Generated Neurovirulence, Antigenicity, and Host Immune Responses

ISRN Virology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-24 ◽  
Author(s):  
Ravi Kant Upadhyay
Keyword(s):  
Immune Responses ◽  
Clinical Care ◽  
Active Immunization ◽  
Target Cells ◽  
Natural Immunity ◽  
Class I Mhc ◽  
Host Immune Responses ◽  
The Central Nervous System ◽  
Behavioral Impairments ◽  
Global Eradication

In response to a JE virus attack, infected body cells start secretion of different cytokines and activate innate immune response. Virus starts neuronal invasion by entering into nerve cells and inflecting the central nervous system. It avoids exposure of body’s natural immunity and generates neurotrophic effects. Virus causes acute susceptibility to CNS and establishes encephalitis syndrome that results in very high fatality in children. In survivors, JEV inhibits the growth and proliferation of NCPs and imposes permanent neuronal disorders like cognitive, motor, and behavioral impairments. However, body cells start TCR mediated interactions, to recognize viral antigens with class I MHC complex on specific target cells, and operate mass killing of virus infected cells by increased CTL activity. Thus, both cell mediated and antibody interactions plays a central role in protection against JEV. In the present review article virus generated neurovirulence, antigenicity, and host immune responses are described in detail. More emphasis is given on diagnosis, clinical care, and active immunization with well-designed potential antiflavivirus vaccines. Further, for achieving an elite success against JEV, global eradication strategies are to be needed for making vaccination program more responsible and effective in endemic areas.

scholarly journals Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant

2021 ◽  
Author(s):  
Jun Zhang ◽  
Tianshu Xiao ◽  
Yongfei Cai ◽  
Christy L. Lavine ◽  
Hanqin Peng ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Intervention Strategies ◽  
Spike Protein ◽  
Target Cells ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Low Levels ◽  
Guide Intervention

AbstractThe Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report here structure, function and antigenicity of its full-length spike (S) trimer in comparison with those of other variants, including Gamma, Kappa, and previously characterized Alpha and Beta. Delta S can fuse membranes more efficiently at low levels of cellular receptor ACE2 and its pseudotyped viruses infect target cells substantially faster than all other variants tested, possibly accounting for its heightened transmissibility. Mutations of each variant rearrange the antigenic surface of the N-terminal domain of the S protein in a unique way, but only cause local changes in the receptor-binding domain, consistent with greater resistance particular to neutralizing antibodies. These results advance our molecular understanding of distinct properties of these viruses and may guide intervention strategies.

scholarly journals A Fusion Peptide in the Spike Protein of MERS Coronavirus

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 825 ◽  
Author(s):  
Entedar A. J. Alsaadi ◽  
Benjamin W. Neuman ◽  
Ian M. Jones
Keyword(s):  
Mammalian Cells ◽  
Middle Eastern ◽  
Membrane Binding ◽  
Protein S ◽  
Syncytium Formation ◽  
Fusion Peptide ◽  
Amino Acid Replacement ◽  
Spike Protein ◽  
S Protein

Coronaviruses represent current and emerging threats for many species, including humans. Middle East respiratory syndrome-related coronavirus (MERS-CoV) is responsible for sporadic infections in mostly Middle Eastern countries, with occasional transfer elsewhere. A key step in the MERS-CoV replication cycle is the fusion of the virus and host cell membranes mediated by the virus spike protein, S. The location of the fusion peptide within the MERS S protein has not been precisely mapped. We used isolated peptides and giant unilamellar vesicles (GUV) to demonstrate membrane binding for a peptide located near the N-terminus of the S2 domain. Key residues required for activity were mapped by amino acid replacement and their relevance in vitro tested by their introduction into recombinant MERS S protein expressed in mammalian cells. Mutations preventing membrane binding in vitro also abolished S-mediated syncytium formation consistent with the identified peptide acting as the fusion peptide for the S protein of MERS-CoV.

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