Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccine.
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ABSTRACT:
SUBMITTER: Kanduc D
PROVIDER: S-EPMC7499017 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccine.
Kanduc Darja D Shoenfeld Yehuda Y
Immunologic research 20200918 5
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Project description:Molecular Dynamics (MD) is a method used to calculate the movement of atoms and molecules broadly applied to several aspects of science. It involves computational simulation, which makes it, at first glance, not easily accessible. The rise of several automated tools to perform molecular simulations has allowed researchers to navigate through the various steps of MD. This enables to elucidate structural properties of proteins that could not be analyzed otherwise, such as the impact of glycosylation. Glycosylation dictates the physicochemical and biological properties of a protein modulating its solubility, stability, resistance to proteolysis, interaction partners, enzymatic activity, binding and recognition. Given the high conformational and compositional diversity of the glycan chains, assessing their influence on the protein structure is challenging using conventional analytical techniques. In this manuscript, we present a step-by-step workflow to build and perform MD analysis of glycoproteins focusing on the SPIKE glycoprotein of SARS-CoV-2 to appraise the impact of glycans in structure stabilization and antibody occlusion.
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Project description:The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a grave threat to global public health and imposes a severe burden on the entire human society. Like other coronaviruses, the SARS-CoV-2 genome encodes spike (S) glycoproteins, which protrude from the surface of mature virions. The S glycoprotein plays essential roles in virus attachment, fusion and entry into the host cell. Surface location of the S glycoprotein renders it a direct target for host immune responses, making it the main target of neutralizing antibodies. In the light of its crucial roles in viral infection and adaptive immunity, the S protein is the focus of most vaccine strategies as well as therapeutic interventions. In this review, we highlight and describe the recent progress that has been made in the biosynthesis, structure, function, and antigenicity of the SARS-CoV-2 S glycoprotein, aiming to provide valuable insights into the design and development of the S protein-based vaccines as well as therapeutics.
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Project description:The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presents an urgent need for an effective vaccine. Molecular characterization of SARS-CoV-2 is critical to the development of effective vaccine and therapeutic strategies. In the present study, we show that the fusion of the SARS-CoV-2 spike protein receptor-binding domain to its transmembrane domain is sufficient to mediate trimerization. Our findings may have implications for vaccine development and therapeutic drug design strategies targeting spike trimerization. As global efforts for developing SARS-CoV-2 vaccines are rapidly underway, we believe this observation is an important consideration for identifying crucial epitopes of SARS-CoV-2.
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Project description:The coronavirus disease 2019 outbreak has become a huge challenge in the human sector for the past two years. The coronavirus is capable of mutating at a higher rate than other viruses. Thus, an approach for creating an effective vaccine is still needed to induce antibodies against multiple variants with lower side effects. Currently, there is a lack of research on designing a multiepitope of the COVID-19 spike protein for the Indonesian population with comprehensive immunoinformatic analysis. Therefore, this study aimed to design a multiepitope-based vaccine for the Indonesian population using an immunoinformatic approach. This study was conducted using the SARS-CoV-2 spike glycoprotein sequences from Indonesia that were retrieved from the GISAID database. Three SARS-CoV-2 sequences, with IDs of EIJK-61453, UGM0002, and B.1.1.7 were selected. The CD8+ cytotoxic T-cell lymphocyte (CTL) epitope, CD4+ helper T lymphocyte (HTL) epitope, B-cell epitope, and IFN-γ production were predicted. After modeling the vaccines, molecular docking, molecular dynamics, in silico immune simulations, and plasmid vector design were performed. The designed vaccine is antigenic, non-allergenic, non-toxic, capable of inducing IFN-γ with a population reach of 86.29% in Indonesia, and has good stability during molecular dynamics and immune simulation. Hence, this vaccine model is recommended to be investigated for further study.
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Project description:Molecular mimicry between viral antigens and host proteins can produce cross-reacting antibodies leading to autoimmunity. The coronavirus SARS-CoV-2 causes COVID-19, a disease curiously resulting in varied symptoms and outcomes, ranging from asymptomatic to fatal. Autoimmunity due to cross-reacting antibodies resulting from molecular mimicry between viral antigens and host proteins may provide an explanation. Thus, we computationally investigated molecular mimicry between SARS-CoV-2 Spike and known epitopes. We discovered molecular mimicry hotspots in Spike and highlight two examples with tentative high autoimmune potential and implications for understanding COVID-19 complications. We show that a TQLPP motif in Spike and thrombopoietin shares similar antibody binding properties. Antibodies cross-reacting with thrombopoietin may induce thrombocytopenia, a condition observed in COVID-19 patients. Another motif, ELDKY, is shared in multiple human proteins, such as PRKG1 involved in platelet activation and calcium regulation, and tropomyosin, which is linked to cardiac disease. Antibodies cross-reacting with PRKG1 and tropomyosin may cause known COVID-19 complications such as blood-clotting disorders and cardiac disease, respectively. Our findings illuminate COVID-19 pathogenesis and highlight the importance of considering autoimmune potential when developing therapeutic interventions to reduce adverse reactions.
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Project description:The SARS-CoV-2 spike protein mediates attachment of the virus to host cell receptor and fusion between the virus and cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection and constitutes the viral component of mRNA based COVID-19 vaccines. Therefore, in this work we assessed the effect of exposure (24 hours) of 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air-liquid interface (ALI) (n=6/experimental group). Corresponding sham exposed samples served as control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes. Exposure of S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p< 0.01). Pathway analysis revealed enriched terms as specific as COVID-19, interferon (IFN) signaling, influenza, Corona virus, anti-viral response in the bro-ALI. Secreted levels of Interleukin (IL) 4 and IL12 were significantly (p<0.05; non-parametric) increased whereas IL6 decreased in the bro-ALI. In case of alv-ALI, enriched terms involving p53, APRIL, tight junction, integrin kinase, IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p<0.05; non-parametric) increased levels of secreted pro-inflammatory cytokines IFNγ, IL1ꞵ, IL2, IL4, IL6, IL8, IL10, IL12, IL13, and tumor necrosis factor alpha were detected in alv-ALI. Altered levels of these cytokines are also associated with lung fibrotic response. Taken together, we observed a typical anti-viral response in the bronchial model whereas a pro-fibrotic response in the alveolar model. Therefore the bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of variants of concern at different lung regions.
2021-12-13 | GSE185657 | GEO
Project description:Vaccine development against the SARS-CoV-2 virus focuses on the principal target of the neutralizing immune response, the spike (S) glycoprotein. Adenovirus-vectored vaccines offer an effective platform for the delivery of viral antigen, but it is important for the generation of neutralizing antibodies that they produce appropriately processed and assembled viral antigen that mimics that observed on the SARS-CoV-2 virus. Here, we describe the structure, conformation, and glycosylation of the S protein derived from the adenovirus-vectored ChAdOx1 nCoV-19/AZD1222 vaccine. We demonstrate native-like post-translational processing and assembly, and reveal the expression of S proteins on the surface of cells adopting the trimeric prefusion conformation. The data presented here confirm the use of ChAdOx1 adenovirus vectors as a leading platform technology for SARS-CoV-2 vaccines.
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Project description:Vaccine development against the SARS-CoV-2 virus focuses on the principal target of the neutralizing immune response, the spike (S) glycoprotein. Adenovirus-vectored vaccines offer an effective platform for the delivery of viral antigen, but it is important for the generation of neutralizing antibodies that they produce appropriately processed and assembled viral antigen that mimics that observed on the SARS-CoV-2 virus. Here, we describe the structure, conformation and glycosylation of the S protein derived from the adenovirus-vectored ChAdOx1 nCoV-19/AZD1222 vaccine. We demonstrate native-like post-translational processing and assembly, and reveal the expression of S proteins on the surface of cells adopting the trimeric prefusion conformation. The data presented here confirms the use of ChAdOx1 adenovirus vectors as a leading platform technology for SARS-CoV-2 vaccines.
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Project description:IntroductionThe development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in record time to cope with the ongoing coronavirus disease 2019 (COVID-19) pandemic has led to uncertainty about their use and the appearance of adverse neurological reactions. The SARS-CoV-2 spike protein (SP) is used to produce neutralizing antibodies and stimulate innate immunity. However, considering the alterations in the nervous system (NS) caused by COVID- 19, cross-reactions are plausible.ObjectiveTo identify peptides in Homo sapiens SP-like proteins involved in myelin and axon homeostasis that may be affected due to molecular mimicry by antibodies and T cells induced by interaction with SP.Materials and methodsA bioinformatics approach was used. To select the H. sapiens proteins to be studied, related biological processes categorized based on gene ontology were extracted through the construction of a protein-protein interaction network. Peripheral myelin protein 22, a major component of myelin in the peripheral nervous system, was used as the query protein. The extracellular domains and regions susceptible to recognition by antibodies were extracted from UniProt. In the study of T cells, linear sequence similarity between H. sapiens proteins and SP was assessed using BLASTp. This study considered the similarity in terms of biochemical groups per residue and affinity to the human major histocompatibility complex (human leukocyte antigen I), which were evaluated using Needle and NetMHCpan 4.1, respectively.ResultsA large number of shared pentapeptides between SP and H. sapiens proteins were identified. However, only a small group of 39 proteins was linked to axon and myelin homeostasis. In particular, some proteins, such as phosphacan, attractin, and teneurin-4, were susceptible targets of B and T cells. Other proteins closely related to myelin components in the NS, such as myelin-associated glycoprotein, were found to share at least one pentamer with SP in extracellular domains.ConclusionProteins involved in the maintenance of nerve conduction in the central and peripheral NS were identified in H. sapiens. Based on these findings, re-evaluation of the vaccine composition is recommended to prevent possible neurological side effects.
| S-EPMC9605789 | biostudies-literature