Immunity evasion: consequence of the N501Y mutation of the SARS-CoV-2 spike glycoprotein.
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ABSTRACT:
SUBMITTER: Uzoeto HO
PROVIDER: S-EPMC8758984 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:SARS-CoV-2 has been spreading around the world for the past year. Recently, several variants such as B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma), which share a key mutation N501Y on the receptor-binding domain (RBD), appear to be more infectious to humans. To understand the underlying mechanism, we used a cell surface-binding assay, a kinetics study, a single-molecule technique, and a computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and a slower dissociation rate. Atomic force microscopy (AFM)-based single-molecule force microscopy (SMFS) consistently quantified the interaction strength of RBD with the mutation as having increased binding probability and requiring increased unbinding force. Molecular dynamics simulations of RBD-ACE2 complexes indicated that the N501Y mutation introduced additional π-π and π-cation interactions that could explain the changes observed by force microscopy. Taken together, these results suggest that the reinforced RBD-ACE2 interaction that results from the N501Y mutation in the RBD should play an essential role in the higher rate of transmission of SARS-CoV-2 variants, and that future mutations in the RBD of the virus should be under surveillance.
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Project description:The COVID-19 pandemic has been continuing for one and a half year and caused a profound effect on human health. Although advanced researches and literatures are gathered, the influences of SARS-CoV-2 on the reproduction systems are largely unknown, especially on the female reproductive functions. The purpose of this study was to investigate the effect of N501Y mutant spike protein of SARS-Cov-2 on oocyte maturation. We demonstrated that the N501Y mutant of SARS-CoV-2 spike protein impaired the mouse oocyte maturation accompanied by abnormal spindle assembly. Furthermore, the mean spindle length and the plate width were significantly increased in the N501Y-treated group compared to the control group. These results indicated the potential impairment of maturation of the oocytes caused by the infection of SARS-CoV-2, albeit current results were derived from mouse oocytes. The present study provided a theoretical basis for the attention of female reproductive health during the COVID-19 pandemic and shed light on the potential risk of SARS-CoV-2 in the successful rate of assisted reproduction.
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Project description:Beginning in the summer of 2020, a variant of SARS-CoV-2, the cause of the COVID-19 pandemic, emerged in the United Kingdom (UK). This B.1.1.7 variant increased rapidly in prevalence among sequenced strains, attributed to an increase in infection and/or transmission efficiency. The UK variant has 19 nonsynonymous mutations across its viral genome including 8 substitutions or deletions in the spike protein, which interacts with cellular receptors to mediate infection and tropism. Here, using a reverse genetics approach, we show that, of the 8 individual spike protein substitutions, only N501Y exhibited consistent fitness gains for replication in the upper airway in the hamster model as well as primary human airway epithelial cells. The N501Y substitution recapitulated the phenotype of enhanced viral transmission seen with the combined 8 UK spike mutations, suggesting it is a major determinant responsible for increased transmission of this variant. Mechanistically, the N501Y substitution improved the affinity of the viral spike protein for cellular receptors. As suggested by its convergent evolution in Brazil and South Africa, our results indicate that N501Y substitution is a major adaptive spike mutation of major concern.
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Project description:mRNA vaccination of individuals with prior SARS-CoV-2 infection provides superior protection against breakthrough infections with variants of concern compared to vaccination in the absence of prior infection. However, the immune mechanisms by which this ‘hybrid immunity’ is generated and maintained are unknown. While genetic variation in spike glycoprotein effectively subverts neutralizing antibodies, spike-specific T cells are generally maintained against SARS-CoV-2 variants. Thus, we comprehensively profiled T cell responses against the S1 and S2 domains of spike glycoprotein in a cohort of SARS-CoV-2-naive or convalescent individuals who received two-dose mRNA vaccine series and were matched by age, sex, and vaccine type. Using flow cytometry, we observed that the overall functional breadth of CD4 T cells as well as polyfunctional Th1 responses were similar between the two groups. However, polyfunctional cytotoxic CD4 T cell responses against both S1 and S2 domains trended higher among convalescent subjects. Multi-modal single-cell RNA sequencing revealed diverse functional programs in spike-specific CD4 and CD8 T cells in both groups. However, convalescent individuals displayed enhanced cytotoxic and antiviral CD8 T cell responses to both S1 and S2 in the absence of cytokine production. Taken together, our data suggest that cytotoxic CD4 and CD8 T cells targeting spike glycoprotein may partially account for hybrid immunity and protection against breakthrough infections with SARS-CoV-2.
2023-03-01 | GSE223236 | GEO
Project description:The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents significant social, economic and political challenges worldwide. SARS-CoV-2 has caused over 3.5 million deaths since late 2019. Mutations in the spike (S) glycoprotein are of particular concern because it harbours the domain which recognises the angiotensin-converting enzyme 2 (ACE2) receptor and is the target for neutralising antibodies. Mutations in the S protein may induce alterations in the surface spike structures, changing the conformational B-cell epitopes and leading to a potential reduction in vaccine efficacy. Here, we summarise how the more important variants of SARS-CoV-2, which include cluster 5, lineages B.1.1.7 (Alpha variant), B.1.351 (Beta), P.1 (B.1.1.28/Gamma), B.1.427/B.1.429 (Epsilon), B.1.526 (Iota) and B.1.617.2 (Delta) confer mutations in their respective spike proteins which enhance viral fitness by improving binding affinity to the ACE2 receptor and lead to an increase in infectivity and transmission. We further discuss how these spike protein mutations provide resistance against immune responses, either acquired naturally or induced by vaccination. This information will be valuable in guiding the development of vaccines and other therapeutics for protection against the ongoing coronavirus disease 2019 (COVID-19) pandemic.
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Project description: Not available
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Project description:Coronavirus Disease of 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has resulted in a massive health crisis across the globe, with some genetic variants gaining enhanced infectivity and competitive fitness, and thus significantly aggravating the global health concern. In this regard, the recent SARS-CoV-2 alpha, beta, and gamma variants (B.1.1.7, B.1.351, and P.1 lineages, respectively) are of great significance in that they contain several mutations that increase their transmission rates as evident from clinical reports. By the end of March 2021, these variants were accounting for about two-thirds of SARS-CoV-2 variants circulating worldwide. Specifically, the N501Y mutation in the S1 spike receptor binding domain (S1-RBD) of these variants have been reported to increase its affinity for ACE2, although the basis for this is not entirely clear yet. Here, we dissect the mechanism underlying the increased binding affinity of the N501Y mutant for ACE2 using molecular dynamics (MD) simulations of the available ACE2-S1-RBD complex structure (6M0J) and show a prolonged and stable interfacial interaction of the N501Y mutant S1-RBD with ACE2 compared to the wild type S1-RBD. Additionally, we find that the N501Y mutant S1-RBD displays altered dynamics that likely aids in its enhanced interaction with ACE2. By elucidating a mechanistic basis for the increased affinity of the N501Y mutant S1-RBD for ACE2, we believe that the results presented here will aid in developing therapeutic strategies against SARS-CoV-2 including designing of therapeutic agents targeting the ACE2-S1-RBD interaction.
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Project description:The B.1.1.7 variant (also known as Alpha) of SARS-CoV-2, the cause of the COVID-19 pandemic, emerged in the UK in the summer of 2020. The prevalence of this variant increased rapidly owing to an increase in infection and/or transmission efficiency1. The Alpha variant contains 19 nonsynonymous mutations across its viral genome, including 8 substitutions or deletions in the spike protein that interacts with cellular receptors to mediate infection and tropism. Here, using a reverse genetics approach, we show that of the 8 individual spike protein substitutions, only N501Y resulted in consistent fitness gains for replication in the upper airway in a hamster model as well as in primary human airway epithelial cells. The N501Y substitution recapitulated the enhanced viral transmission phenotype of the eight mutations in the Alpha spike protein, suggesting that it is a major determinant of the increased transmission of the Alpha variant. Mechanistically, the N501Y substitution increased the affinity of the viral spike protein for cellular receptors. As suggested by its convergent evolution in Brazil, South Africa and elsewhere2,3, our results indicate that N501Y substitution is an adaptive spike mutation of major concern.
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Project description:Responsible for more than 4.9 million deaths so far, COVID-19, caused by SARS-CoV-2, is instigating devastating effects on the global health care system whose impacts could be longer for the years to come. Acquiring a comprehensive knowledge of host-virus interaction is critical for designing effective vaccines and/or drugs. Understanding the evolution of the virus and the impact of genetic variability on host immune evasion and vaccine efficacy is helpful to design novel strategies to minimize the effects of the emerging variants of concern (VOC). Most vaccines under development and/or in current use target the spike protein owning to its unique function of host receptor binding, relatively conserved nature, potent immunogenicity in inducing neutralizing antibodies, and being a good target of T cell responses. However, emerging SARS-CoV-2 strains are exhibiting variability on the spike protein which could affect the efficacy of vaccines and antibody-based therapies in addition to enhancing viral immune evasion mechanisms. Currently, the degree to which mutations on the spike protein affect immunity and vaccination, and the ability of the current vaccines to confer protection against the emerging variants attracts much attention. This review discusses the implications of SARS-CoV-2 spike protein mutations on immune evasion and vaccine-induced immunity and forward directions which could contribute to future studies focusing on designing effective vaccines and/or immunotherapies to consider viral evolution. Combining vaccines derived from different regions of the spike protein that boost both the humoral and cellular wings of adaptive immunity could be the best options to cope with the emerging VOC.
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Project description:The SARS-CoV-2 is an RNA-based virus and the most vital step of its survival is the attachment to hACE2 through its spike protein. Although SARS-CoV-2 has the ability to maintain high accurate replication and it can be accepted as a low mutation risked virus, it already showed more than nine thousand mutations in spike protein, of which 44 mutations are located within a 3.2 Å interacting distance from the hACE2 receptor. Mutations on spike protein, N501Y and N501T raised serious concerns for higher transmissibility and resistance towards current vaccines. In the current study, the mutational outcomes of N501Y and N501T on the hACE2-SARS CoV-2 spike protein complexation were analyzed by employing all-atom classic molecular dynamics (MD) simulations. These simulations revealed that both N501Y and N501T mutations increased the binding strength of spike protein to the host hACE2, predicted by binding free energy analysis via MM/GBSA rescoring scheme. This study highlights the importance of energy-based analysis for identifying mutational outcomes and will shed light on handling long-term and effective treatment strategies including repurposing anti-viral drugs, anti-SARS-CoV-2 antibodies, vaccines, and antisense based-therapies.
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