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1.
BMC Genom Data ; 23(1): 27, 2022 Apr 08.
Article in English | MEDLINE | ID: covidwho-1779595

ABSTRACT

BACKGROUND: The factors driving the late phase of COVID-19 are still poorly understood. However, autoimmunity is an evolving theme in COVID-19's pathogenesis. Additionally, deregulation of human retroelements (RE) is found in many viral infections, and has also been reported in COVID-19. RESULTS: Unexpectedly, coronaviruses (CoV) - including SARS-CoV-2 - harbour many RE-identical sequences (up to 35 base pairs), and some of these sequences are part of SARS-CoV-2 epitopes associated to COVID-19 severity. Furthermore, RE are expressed in healthy controls and human cells and become deregulated after SARS-CoV-2 infection, showing mainly changes in long interspersed nuclear element (LINE1) expression, but also in endogenous retroviruses. CONCLUSION: CoV and human RE share coding sequences, which are targeted by antibodies in COVID-19 and thus could induce an autoimmune loop by molecular mimicry.


Subject(s)
COVID-19 , SARS-CoV-2 , Epitopes , Humans , Molecular Mimicry , Retroelements/genetics , SARS-CoV-2/genetics
2.
Trends Immunol ; 43(4): 296-308, 2022 04.
Article in English | MEDLINE | ID: covidwho-1763781

ABSTRACT

Guillain-Barré syndrome (GBS) is a rapidly progressive, monophasic, and potentially devastating immune-mediated neuropathy in humans. Preceding infections trigger the production of cross-reactive antibodies against gangliosides concentrated in human peripheral nerves. GBS is elicited by at least five distinct common bacterial and viral pathogens, speaking to the notion of polymicrobial disease causation. This opinion emphasizes that GBS is the best-supported example of true molecular mimicry at the B cell level. Moreover, we argue that mechanistically, single and multiplexed microbial carbohydrate epitopes induce IgM, IgA, and IgG subclasses in ways that challenge the classic concept of thymus-dependent (TD) versus thymus-independent (TI) antibody responses in GBS. Finally, we discuss how GBS can be exemplary for driving innovation in diagnostics and immunotherapy for other antibody-driven neurological diseases.


Subject(s)
Guillain-Barre Syndrome , Molecular Mimicry , Antibody Formation , Autoantibodies , Gangliosides , Guillain-Barre Syndrome/etiology , Guillain-Barre Syndrome/therapy , Humans , Immunoglobulin G
3.
Science ; 375(6579): 449-454, 2022 Jan 28.
Article in English | MEDLINE | ID: covidwho-1723472

ABSTRACT

Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against SARS-CoV-2 variants and future zoonotic sarbecoviruses. We describe the isolation and characterization of a human monoclonal antibody, designated S2K146, that broadly neutralizes viruses belonging to SARS-CoV- and SARS-CoV-2-related sarbecovirus clades which use ACE2 as an entry receptor. Structural and functional studies show that most of the virus residues that directly bind S2K146 are also involved in binding to ACE2. This allows the antibody to potently inhibit receptor attachment. S2K146 protects against SARS-CoV-2 Beta challenge in hamsters and viral passaging experiments reveal a high barrier for emergence of escape mutants, making it a good candidate for clinical development. The conserved ACE2-binding residues present a site of vulnerability that might be leveraged for developing vaccines eliciting broad sarbecovirus immunity.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Viral/immunology , Betacoronavirus/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/therapy , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/metabolism , Antibody Affinity , Broadly Neutralizing Antibodies/chemistry , Broadly Neutralizing Antibodies/metabolism , Broadly Neutralizing Antibodies/therapeutic use , COVID-19/immunology , Cross Reactions , Cryoelectron Microscopy , Epitopes , Humans , Immune Evasion , Mesocricetus , Models, Molecular , Molecular Mimicry , Mutation , Protein Conformation , Protein Domains , Receptors, Coronavirus/chemistry , Receptors, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
4.
Brief Bioinform ; 23(2)2022 03 10.
Article in English | MEDLINE | ID: covidwho-1713564

ABSTRACT

The development of autoimmune diseases following SARS-CoV-2 infection, including multisystem inflammatory syndrome, has been reported, and several mechanisms have been suggested, including molecular mimicry. We developed a scalable, comparative immunoinformatics pipeline called cross-reactive-epitope-search-using-structural-properties-of-proteins (CRESSP) to identify cross-reactive epitopes between a collection of SARS-CoV-2 proteomes and the human proteome using the structural properties of the proteins. Overall, by searching 4 911 245 proteins from 196 352 SARS-CoV-2 genomes, we identified 133 and 648 human proteins harboring potential cross-reactive B-cell and CD8+ T-cell epitopes, respectively. To demonstrate the robustness of our pipeline, we predicted the cross-reactive epitopes of coronavirus spike proteins, which were recognized by known cross-neutralizing antibodies. Using single-cell expression data, we identified PARP14 as a potential target of intermolecular epitope spreading between the virus and human proteins. Finally, we developed a web application (https://ahs2202.github.io/3M/) to interactively visualize our results. We also made our pipeline available as an open-source CRESSP package (https://pypi.org/project/cressp/), which can analyze any two proteomes of interest to identify potentially cross-reactive epitopes between the proteomes. Overall, our immunoinformatic resources provide a foundation for the investigation of molecular mimicry in the pathogenesis of autoimmune and chronic inflammatory diseases following COVID-19.


Subject(s)
Computational Biology/methods , Epitopes/chemistry , Epitopes/immunology , SARS-CoV-2/immunology , Software , Viral Proteins/chemistry , Viral Proteins/immunology , Algorithms , Cross Reactions/immunology , Epitopes, B-Lymphocyte , Epitopes, T-Lymphocyte , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/immunology , Models, Molecular , Molecular Mimicry , Neural Networks, Computer , Proteome , Proteomics/methods , Structure-Activity Relationship , Web Browser
5.
Viruses ; 14(2)2022 02 14.
Article in English | MEDLINE | ID: covidwho-1687052

ABSTRACT

The evolution of the SARS-CoV-2 virus during the COVID-19 pandemic was accompanied by the emergence of new heavily mutated viral variants with increased infectivity and/or resistance to detection by the human immune system. To respond to the urgent need for advanced methods and materials to empower a better understanding of the mechanisms of virus's adaptation to human host cells and to the immuno-resistant human population, we suggested using recombinant filamentous bacteriophages, displaying on their surface foreign peptides termed "mimotopes", which mimic the structure of viral receptor-binding sites on the viral spike protein and can serve as molecular probes in the evaluation of molecular mechanisms of virus infectivity. In opposition to spike-binding antibodies that are commonly used in studying the interaction of the ACE2 receptor with SARS-CoV-2 variants in vitro, phage spike mimotopes targeted to other cellular receptors would allow discovery of their role in viral infection in vivo using cell culture, tissue, organs, or the whole organism. Phage mimotopes of the SARS-CoV-2 Spike S1 protein have been developed using a combination of phage display and molecular mimicry concepts, termed here "phage mimicry", supported by bioinformatics methods. The key elements of the phage mimicry concept include: (1) preparation of a collection of p8-type (landscape) phages, which interact with authentic active receptors of live human cells, presumably mimicking the binding interactions of human coronaviruses such as SARS-CoV-2 and its variants; (2) discovery of closely related amino acid clusters with similar 3D structural motifs on the surface of natural ligands (FGF1 and NRP1), of the model receptor of interest FGFR and the S1 spike protein; and (3) an ELISA analysis of the interaction between candidate phage mimotopes with FGFR3 (a potential alternative receptor) in comparison with ACE2 (the authentic receptor).


Subject(s)
Bacteriophages/genetics , Cell Surface Display Techniques/methods , Molecular Mimicry , Receptors, Cell Surface/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Bacteriophages/metabolism , Binding Sites , Humans , Protein Binding , Receptors, Cell Surface/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment
7.
J Neuroinflammation ; 18(1): 245, 2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1496192

ABSTRACT

Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection. In this systematic review, we have identified eight SARS-CoV-2-associated cases of anti-NMDA receptor encephalitis. All had cerebrospinal fluid antibodies against the NMDA receptor and a recent onset of working memory deficits, altered mental status, or psychiatric symptoms, such as confusion, agitation, auditory hallucination, catatonia and speech dysfunction. All patients received high-dose steroid and immunoglobulin therapeutics and conditions improved in each case. These findings suggest that clinical attention should be paid to warning signs of autoimmune encephalitis in severe COVID-19 cases. If characteristic features of autoimmune encephalitis are present, autoantibody diagnostics should be performed and confirmed cases should be treated with immunotherapy to minimize neurological impairments.


Subject(s)
Anti-N-Methyl-D-Aspartate Receptor Encephalitis/virology , COVID-19/complications , Mental Disorders/virology , Receptors, N-Methyl-D-Aspartate/immunology , Adolescent , Adult , Autoantibodies/immunology , COVID-19/immunology , Child , Female , Humans , Infant , Male , Middle Aged , Molecular Mimicry , SARS-CoV-2/immunology , Young Adult
8.
J Autoimmun ; 125: 102741, 2021 12.
Article in English | MEDLINE | ID: covidwho-1482678

ABSTRACT

The COVID-19 pandemic is still raging across the world and vaccination is expected to lead us out of this pandemic. Although the efficacy of the vaccines is beyond doubt, safety still remains a concern. We report a case of a 65-year-old woman who experienced acute severe autoimmune hepatitis two weeks after receiving the first dose of Moderna-COVID-19 vaccine. Serum immunoglobulin G was elevated and antinuclear antibody was positive (1:100, speckled pattern). Liver histology showed a marked expansion of the portal tracts, severe interface hepatitis and multiple confluent foci of lobular necrosis. She started treatment with prednisolone, with a favorable clinical and analytical evolution. Some recent reports have been suggested that COVID-19 vaccination can lead to the development of autoimmune diseases. It is speculated that the vaccine can disturb self-tolerance and trigger autoimmune responses through cross-reactivity with host cells. Therefore, healthcare providers must remain vigilant during mass COVID-19 vaccination.


Subject(s)
/adverse effects , COVID-19/prevention & control , Hepatitis, Autoimmune/etiology , Jaundice/etiology , Vaccination/adverse effects , Antibodies, Antinuclear/blood , Bilirubin/blood , Female , Fibrosis/pathology , Hepatitis, Autoimmune/immunology , Humans , Jaundice/diagnosis , Liver/enzymology , Middle Aged , Molecular Mimicry/immunology , Prednisolone/therapeutic use , SARS-CoV-2/immunology
9.
J Autoimmun ; 125: 102738, 2021 12.
Article in English | MEDLINE | ID: covidwho-1466582

ABSTRACT

Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccines against it could represent new environmental triggers for AIED. We report a patient, with history of vitiligo vulgaris and 8 years of type 2 diabetes, who came to our institution because of fever, weight loss, asthenia and thyrotoxicosis occurred 4 weeks later the administration of BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Clinical, biochemical and instrumental work-up demonstrated Graves' disease and autoimmune diabetes mellitus. The occurrence of these disorders could be explained through different mechanism such as autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), mRNA "self-adjuvant" effect, molecular mimicry between human and viral proteins and immune disruption from external stimuli. However further studies are needed to better understand the underlying pathogenesis of AIED following SARS-CoV-2 vaccine.


Subject(s)
/adverse effects , COVID-19/prevention & control , Diabetes Mellitus, Type 1/etiology , Graves Disease/etiology , Molecular Mimicry/immunology , Adjuvants, Immunologic/adverse effects , Autoantibodies/blood , C-Peptide/blood , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glycated Hemoglobin A/analysis , Glycemic Control , Humans , Male , Middle Aged , SARS-CoV-2/immunology , Thyrotoxicosis/pathology , Vitiligo/pathology
10.
Mol Syst Biol ; 17(9): e10079, 2021 09.
Article in English | MEDLINE | ID: covidwho-1406892

ABSTRACT

We modeled 3D structures of all SARS-CoV-2 proteins, generating 2,060 models that span 69% of the viral proteome and provide details not available elsewhere. We found that ˜6% of the proteome mimicked human proteins, while ˜7% was implicated in hijacking mechanisms that reverse post-translational modifications, block host translation, and disable host defenses; a further ˜29% self-assembled into heteromeric states that provided insight into how the viral replication and translation complex forms. To make these 3D models more accessible, we devised a structural coverage map, a novel visualization method to show what is-and is not-known about the 3D structure of the viral proteome. We integrated the coverage map into an accompanying online resource (https://aquaria.ws/covid) that can be used to find and explore models corresponding to the 79 structural states identified in this work. The resulting Aquaria-COVID resource helps scientists use emerging structural data to understand the mechanisms underlying coronavirus infection and draws attention to the 31% of the viral proteome that remains structurally unknown or dark.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Host-Pathogen Interactions/genetics , Protein Processing, Post-Translational , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Transport Systems, Neutral/chemistry , Amino Acid Transport Systems, Neutral/genetics , Amino Acid Transport Systems, Neutral/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Binding Sites , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Computational Biology/methods , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Coronavirus Envelope Proteins/metabolism , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/metabolism , Humans , Mitochondrial Membrane Transport Proteins/chemistry , Mitochondrial Membrane Transport Proteins/genetics , Mitochondrial Membrane Transport Proteins/metabolism , Models, Molecular , Molecular Mimicry , Neuropilin-1/chemistry , Neuropilin-1/genetics , Neuropilin-1/metabolism , Phosphoproteins/chemistry , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Interaction Mapping/methods , Protein Multimerization , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/genetics , Viral Matrix Proteins/metabolism , Viroporin Proteins/chemistry , Viroporin Proteins/genetics , Viroporin Proteins/metabolism , Virus Replication
11.
J Med Virol ; 93(9): 5350-5357, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1384240

ABSTRACT

PARP14 and PARP9 play a key role in macrophage immune regulation. SARS-CoV-2 is an emerging viral disease that triggers hyper-inflammation known as a cytokine storm. In this study, using in silico tools, we hypothesize about the immunological phenomena of molecular mimicry between SARS-CoV-2 Nsp3 and the human PARP14 and PARP9. The results showed an epitope of SARS-CoV-2 Nsp3 protein that contains consensus sequences for both human PARP14 and PARP9 that are antigens for MHC Classes 1 and 2, which can potentially induce an immune response against human PARP14 and PARP9; while its depletion causes a hyper-inflammatory state in SARS-CoV-2 patients.


Subject(s)
COVID-19/immunology , Coronavirus Papain-Like Proteases/chemistry , Cytokine Release Syndrome/immunology , Neoplasm Proteins/chemistry , Poly(ADP-ribose) Polymerases/chemistry , SARS-CoV-2/immunology , Amino Acid Sequence , Binding Sites , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Computer Simulation , Consensus Sequence , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/immunology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , Gene Expression , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/chemistry , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Macrophages/immunology , Macrophages/virology , Molecular Docking Simulation , Molecular Mimicry , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/immunology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sequence Alignment , Sequence Homology, Amino Acid , Thermodynamics
12.
Brain ; 144(5): e43, 2021 06 22.
Article in English | MEDLINE | ID: covidwho-1387731
14.
Bioengineered ; 12(1): 4407-4419, 2021 12.
Article in English | MEDLINE | ID: covidwho-1373615

ABSTRACT

Widespread infection due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has led to a global pandemic. Currently, various approaches are being taken up to develop vaccines and therapeutics to treat SARS-CoV2 infection. Consequently, the S protein has become an important target protein for developing vaccines and therapeutics against SARS-CoV2. However, the highly infective nature of SARS-CoV2 restricts experimentation with the virus to highly secure BSL3 facilities. The availability of fusion-enabled, nonreplicating, and nonbiohazardous mimics of SARS-CoV2 virus fusion, containing the viral S or S and M protein in their native conformation on mammalian cells, can serve as a useful substitute for studying viral fusion for testing various inhibitors of viral fusion. This would avoid the use of the BSL3 facility for fusion studies required to develop therapeutics. In the present study, we have developed SARS-CoV2 virus fusion mimics (SCFMs) using mammalian cells transfected with constructs coding for S or S and M protein. The fusogenic property of the mimic(s) and their interaction with the functional human ACE2 receptors was confirmed experimentally. We have also shown that such mimics can easily be used in an inhibition assay. These mimic(s) can be easily prepared on a large scale, and such SCFMs can serve as an invaluable resource for viral fusion inhibition assays and in vitro screening of antiviral agents, which can be shared/handled between labs/facilities without worrying about any biohazard while working under routine laboratory conditions, avoiding the use of BSL3 laboratory.Abbreviations :SCFM: SARS-CoV2 Virus Fusion Mimic; ACE2: Angiotensin-Converting Enzyme 2; hACE2: Human Angiotensin-Converting enzyme 2; MEF: Mouse Embryonic Fibroblasts; HBSS: Hanks Balanced Salt Solution; FBS: Fetal Bovine Serum.


Subject(s)
Antibodies, Neutralizing/pharmacology , Containment of Biohazards/methods , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Viral Matrix Proteins/antagonists & inhibitors , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Chlorocebus aethiops , Embryo, Mammalian , Fibroblasts/drug effects , Fibroblasts/virology , Gene Expression , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , HEK293 Cells , Humans , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , MCF-7 Cells , Mice , Molecular Mimicry , Plasmids/chemistry , Plasmids/metabolism , Primary Cell Culture , Protein Binding , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Transfection , Vero Cells , Viral Matrix Proteins/genetics , Viral Matrix Proteins/metabolism
15.
Circulation ; 144(6): 471-484, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1365256

ABSTRACT

Myocarditis has been recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccinations, especially in young adult and adolescent males. According to the US Centers for Disease Control and Prevention, myocarditis/pericarditis rates are ≈12.6 cases per million doses of second-dose mRNA vaccine among individuals 12 to 39 years of age. In reported cases, patients with myocarditis invariably presented with chest pain, usually 2 to 3 days after a second dose of mRNA vaccination, and had elevated cardiac troponin levels. ECG was abnormal with ST elevations in most, and cardiac MRI was suggestive of myocarditis in all tested patients. There was no evidence of acute COVID-19 or other viral infections. In 1 case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-antigens and frequency of natural killer cells were increased. Although the mechanisms for development of myocarditis are not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have been proposed. The reasons for male predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune response and myocarditis, and also underdiagnosis of cardiac disease in women. Almost all patients had resolution of symptoms and signs and improvement in diagnostic markers and imaging with or without treatment. Despite rare cases of myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore, COVID-19 vaccination is recommended for everyone ≥12 years of age.


Subject(s)
Autoantigens/immunology , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Myocarditis/chemically induced , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Biomarkers , COVID-19/epidemiology , COVID-19/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Female , Humans , Male , Molecular Mimicry/immunology , Myocarditis/immunology , Sex Factors
16.
Am J Reprod Immunol ; 86(6): e13494, 2021 12.
Article in English | MEDLINE | ID: covidwho-1360445

ABSTRACT

INTRODUCTION: Oogenesis, the process of egg production by the ovary, involves a complex differentiation program leading to the production of functional oocytes. This process comprises a sequential pathway of steps that are finely regulated. The question related to SARS-CoV-2 infection and fertility has been evoked for several reasons, including the mechanism of molecular mimicry, which may contribute to female infertility by leading to the generation of deleterious autoantibodies, possibly contributing to the onset of an autoimmune disease in infected patients. OBJECTIVE: The immunological potential of the peptides shared between SARS-CoV-2 spike glycoprotein and oogenesis-related proteins; Thus we planned a systematic study to improve our understanding of the possible effects of SARS-CoV-2 infection on female fertility using the angle of molecular mimicry as a starting point. METHODS: A library of 82 human proteins linked to oogenesis was assembled at random from UniProtKB database using oogenesis, uterine receptivity, decidualization, and placentation as a key words. For the analyses, an artificial polyprotein was built by joining the 82 a sequences of the oogenesis-associated proteins. These were analyzed by searching the Immune Epitope DataBase for immunoreactive SARS-CoV-2 spike glycoprotein epitopes hosting the shared pentapeptides. RESULTS: SARS-CoV-2 spike glycoprotein was found to share 41 minimal immune determinants, that is, pentapeptides, with 27 human proteins that relate to oogenesis, uterine receptivity, decidualization, and placentation. All the shared pentapeptides that we identified, with the exception of four, are also present in SARS-CoV-2 spike glycoprotein-derived epitopes that have been experimentally validated as immunoreactive.


Subject(s)
Molecular Mimicry , Oogenesis/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Epitopes , Female , Humans
17.
Circulation ; 144(6): 471-484, 2021 08 10.
Article in English | MEDLINE | ID: covidwho-1318235

ABSTRACT

Myocarditis has been recognized as a rare complication of coronavirus disease 2019 (COVID-19) mRNA vaccinations, especially in young adult and adolescent males. According to the US Centers for Disease Control and Prevention, myocarditis/pericarditis rates are ≈12.6 cases per million doses of second-dose mRNA vaccine among individuals 12 to 39 years of age. In reported cases, patients with myocarditis invariably presented with chest pain, usually 2 to 3 days after a second dose of mRNA vaccination, and had elevated cardiac troponin levels. ECG was abnormal with ST elevations in most, and cardiac MRI was suggestive of myocarditis in all tested patients. There was no evidence of acute COVID-19 or other viral infections. In 1 case, a cardiomyopathy gene panel was negative, but autoantibody levels against certain self-antigens and frequency of natural killer cells were increased. Although the mechanisms for development of myocarditis are not clear, molecular mimicry between the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and self-antigens, trigger of preexisting dysregulated immune pathways in certain individuals, immune response to mRNA, and activation of immunologic pathways, and dysregulated cytokine expression have been proposed. The reasons for male predominance in myocarditis cases are unknown, but possible explanations relate to sex hormone differences in immune response and myocarditis, and also underdiagnosis of cardiac disease in women. Almost all patients had resolution of symptoms and signs and improvement in diagnostic markers and imaging with or without treatment. Despite rare cases of myocarditis, the benefit-risk assessment for COVID-19 vaccination shows a favorable balance for all age and sex groups; therefore, COVID-19 vaccination is recommended for everyone ≥12 years of age.


Subject(s)
Autoantigens/immunology , COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Myocarditis/chemically induced , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Biomarkers , COVID-19/epidemiology , COVID-19/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Female , Humans , Male , Molecular Mimicry/immunology , Myocarditis/immunology , Sex Factors
18.
Mol Immunol ; 137: 105-113, 2021 09.
Article in English | MEDLINE | ID: covidwho-1294069

ABSTRACT

Underlying mechanisms of multi-organ manifestations and exacerbated inflammation in COVID-19 are yet to be delineated. The hypothesis of SARS-CoV-2 triggering autoimmunity is gaining attention and, in the present study, we have identified 28 human proteins harbouring regions homologous to SARS-CoV-2 peptides that could possibly be acting as autoantigens in COVID-19 patients displaying autoimmune conditions. Interestingly, these conserved regions are amongst the experimentally validated B cell epitopes of SARS-CoV-2 proteins. The reported human proteins have demonstrated presence of autoantibodies against them in typical autoimmune conditions which may explain the frequent occurrence of autoimmune conditions following SARS-CoV-2 infection. Moreover, the proposed autoantigens' widespread tissue distribution is suggestive of their involvement in multi-organ manifestations via molecular mimicry. We opine that our report may aid in directing subsequent necessary antigen-specific studies, results of which would be of long-term relevance in management of extrapulmonary symptoms of COVID-19.


Subject(s)
Autoantigens/immunology , Autoimmune Diseases/complications , COVID-19/etiology , Epitopes, B-Lymphocyte/immunology , SARS-CoV-2/immunology , Autoantibodies/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/virology , Autoimmunity/immunology , COVID-19/immunology , COVID-19/pathology , Humans , Molecular Mimicry/immunology
19.
Cell Stress Chaperones ; 26(4): 611-616, 2021 07.
Article in English | MEDLINE | ID: covidwho-1225062

ABSTRACT

A few reports suggest that molecular mimicry can have a role in determining the more severe and deadly forms of COVID-19, inducing endothelial damage, disseminated intravascular coagulation, and multiorgan failure. Heat shock proteins/molecular chaperones can be involved in these molecular mimicry phenomena. However, tumor cells can display on their surface heat shock proteins/molecular chaperones that are mimicked by SARS-CoV-2 molecules (including the Spike protein), similarly to what happens in other bacterial or viral infections. Since molecular mimicry between SARS-CoV-2 and tumoral proteins can elicit an immune reaction in which antibodies or cytotoxic cells produced against the virus cross-react with the tumor cells, we want to prompt clinical studies to evaluate the impact of SARS-CoV-2 infection on prognosis and follow up of various forms of tumors. These topics, including a brief historical overview, are discussed in this paper.


Subject(s)
COVID-19/immunology , COVID-19/virology , Immunity , Molecular Mimicry , Neoplasms/immunology , SARS-CoV-2/physiology , Viral Proteins/metabolism , Humans
20.
Proteins ; 89(9): 1065-1078, 2021 09.
Article in English | MEDLINE | ID: covidwho-1222689

ABSTRACT

SARS coronavirus 2 is neutralized by proteins that block receptor-binding sites on spikes that project from the viral envelope. In particular, substantial research investment has advanced monoclonal antibody therapies to the clinic where they have shown partial efficacy in reducing viral burden and hospitalization. An alternative is to use the host entry receptor, angiotensin-converting enzyme 2 (ACE2), as a soluble decoy that broadly blocks SARS-associated coronaviruses with limited potential for viral escape. Here, we summarize efforts to engineer higher affinity variants of soluble ACE2 that rival the potency of affinity-matured antibodies. Strategies have also been used to increase the valency of ACE2 decoys for avid spike interactions and to improve pharmacokinetics via IgG fusions. Finally, the intrinsic catalytic activity of ACE2 for the turnover of the vasoconstrictor angiotensin II may directly address COVID-19 symptoms and protect against lung and cardiovascular injury, conferring dual mechanisms of action unachievable by monoclonal antibodies. Soluble ACE2 derivatives therefore have the potential to be next generation therapeutics for addressing the immediate needs of the current pandemic and possible future outbreaks.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Molecular Mimicry , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Humans , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin Fc Fragments/metabolism , Mutation , Nanoparticles/chemistry , Nanoparticles/metabolism , Protein Binding , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/metabolism , SARS-CoV-2/chemistry
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