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1.
PLoS Comput Biol ; 18(2): e1009726, 2022 02.
Article in English | MEDLINE | ID: covidwho-1753172

ABSTRACT

The massive assessment of immune evasion due to viral mutations that increase COVID-19 susceptibility can be computationally facilitated. The adaptive cytotoxic T response is critical during primary infection and the generation of long-term protection. Here, potential HLA class I epitopes in the SARS-CoV-2 proteome were predicted for 2,915 human alleles of 71 families using the netMHCIpan EL algorithm. Allele families showed extreme epitopic differences, underscoring genetic variability of protective capacity between humans. Up to 1,222 epitopes were associated with any of the twelve supertypes, that is, allele clusters covering 90% population. Next, from all mutations identified in ~118,000 viral NCBI isolates, those causing significant epitope score reduction were considered epitope escape mutations. These mutations mainly involved non-conservative substitutions at the second and C-terminal position of the ligand core, or total ligand removal by large recurrent deletions. Escape mutations affected 47% of supertype epitopes, which in 21% of cases concerned isolates from two or more sub-continental areas. Some of these changes were coupled, but never surpassed 15% of evaded epitopes for the same supertype in the same isolate, except for B27. In contrast to most supertypes, eight allele families mostly contained alleles with few SARS-CoV-2 ligands. Isolates harboring cytotoxic escape mutations for these families co-existed geographically within sub-Saharan and Asian populations enriched in these alleles according to the Allele Frequency Net Database. Collectively, our findings indicate that escape mutation events have already occurred for half of HLA class I supertype epitopes. However, it is presently unlikely that, overall, it poses a threat to the global population. In contrast, single and double mutations for susceptible alleles may be associated with viral selective pressure and alarming local outbreaks. The integration of genomic, geographical and immunoinformatic information eases the surveillance of variants potentially affecting the global population, as well as minority subpopulations.


Subject(s)
COVID-19 , Genome, Viral , Immune Evasion , Mutation , SARS-CoV-2 , COVID-19/immunology , COVID-19/virology , Epitopes/genetics , Epitopes/immunology , Gene Frequency , Genome, Viral/genetics , Genome, Viral/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Mutation/genetics , Mutation/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Viral Proteins/genetics , Viral Proteins/immunology
2.
J Virol ; 94(13)2020 06 16.
Article in English | MEDLINE | ID: covidwho-1723544

ABSTRACT

Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/virology , Histocompatibility Testing/methods , Pneumonia, Viral/virology , Amino Acid Sequence , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Epitopes, T-Lymphocyte/immunology , Genetic Variation , Genotype , Haplotypes , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immunity, Innate/immunology , Pandemics , Pneumonia, Viral/immunology , SARS-CoV-2 , T-Lymphocytes/immunology
3.
Front Immunol ; 13: 769900, 2022.
Article in English | MEDLINE | ID: covidwho-1705660

ABSTRACT

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).


Subject(s)
COVID-19/pathology , HLA-B51 Antigen/genetics , HLA-C Antigens/genetics , SARS-CoV-2/immunology , Severity of Illness Index , Adult , Age Factors , Armenia , Female , Gene Frequency/genetics , HLA-B51 Antigen/immunology , HLA-C Antigens/immunology , Heterozygote , Histocompatibility Antigens Class I/genetics , Humans , Male , Middle Aged , Pandemics , Risk , Sex Factors , Viral Proteins/immunology
4.
Front Immunol ; 13: 832889, 2022.
Article in English | MEDLINE | ID: covidwho-1686488

ABSTRACT

The potential effect of emerging SARS-CoV-2 variants on vaccine efficacy is an issue of critical importance. In this study, the possible impact of mutations that facilitate virus escape from the cytotoxic and the helper cellular immune responses in the new SARS-CoV-2 Omicron variant of concern was analyzed for the 551 and 41 most abundant HLA class I and II alleles, respectively. Computational prediction showed that almost all of these 592 alleles, which cover >90% of the human population, contain enough epitopes without escape mutations in the emerging SARS-CoV-2 Omicron variant of concern. These data suggest that both cytotoxic and helper cellular immune protection elicited by currently licensed vaccines are virtually unaffected by the highly contagious SARS-CoV-2 Omicron variant of concern.


Subject(s)
COVID-19/immunology , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class I/immunology , Immunity, Cellular/immunology , SARS-CoV-2/immunology , Epitopes, T-Lymphocyte/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class II/genetics , Humans , Immunogenicity, Vaccine/immunology , Mutation , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
5.
Front Immunol ; 12: 769442, 2021.
Article in English | MEDLINE | ID: covidwho-1686473

ABSTRACT

The prevention of the COVID-19 pandemic is highly complicated by the prevalence of asymptomatic and recurrent infection. Many previous immunological studies have focused on symptomatic and convalescent patients, while the immune responses in asymptomatic patients and re-detectable positive cases remain unclear. Here we comprehensively analyzed the peripheral T-cell receptor (TCR) repertoire of 54 COVID-19 patients in different courses, including asymptomatic, symptomatic, convalescent, and re-detectable positive cases. We identified a set of V-J gene combinations characterizing the upward immune responses through asymptomatic and symptomatic courses. Furthermore, some of these V-J combinations could be awakened in the re-detectable positive cases, which may help predict the risk of recurrent infection. Therefore, TCR repertoire examination has the potential to strengthen the clinical surveillance and the immunotherapy development for COVID-19.


Subject(s)
COVID-19/pathology , Immunoglobulin J-Chains/genetics , Immunoglobulin Variable Region/genetics , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adaptive Immunity/genetics , Adaptive Immunity/immunology , Adult , Aged , Asymptomatic Infections , COVID-19/immunology , Female , Gene Expression/genetics , Histocompatibility Antigens Class I/genetics , Humans , Male , Middle Aged , Receptors, Antigen, T-Cell/immunology , Severity of Illness Index , Young Adult
6.
Rev Med Virol ; 31(6): e2236, 2021 11.
Article in English | MEDLINE | ID: covidwho-1573896

ABSTRACT

Modifications in HLA-I expression are found in many viral diseases. They represent one of the immune evasion strategies most widely used by viruses to block antigen presentation and NK cell response, and SARS-CoV-2 is no exception. These alterations result from a combination of virus-specific factors, genetically encoded mechanisms, and the status of host defences and range from loss or upregulation of HLA-I molecules to selective increases of HLA-I alleles. In this review, I will first analyse characteristic features of altered HLA-I expression found in SARS-CoV-2. I will then discuss the potential factors underlying these defects, focussing on HLA-E and class-I-related (like) molecules and their receptors, the most documented HLA-I alterations. I will also draw attention to potential differences between cells transfected to express viral proteins and those presented as part of authentic infection. Consideration of these factors and others affecting HLA-I expression may provide us with improved possibilities for research into cellular immunity against viral variants.


Subject(s)
Antigenic Variation , COVID-19/immunology , Clonal Anergy , Histocompatibility Antigens Class I/immunology , Immune Evasion , SARS-CoV-2/genetics , Alleles , COVID-19/pathology , COVID-19/virology , Cytokines/genetics , Cytokines/immunology , Cytotoxicity, Immunologic , Gene Expression , Histocompatibility Antigens Class I/genetics , Humans , Immunity, Cellular , Killer Cells, Natural/immunology , Killer Cells, Natural/virology , NK Cell Lectin-Like Receptor Subfamily C/genetics , NK Cell Lectin-Like Receptor Subfamily C/immunology , NK Cell Lectin-Like Receptor Subfamily D/genetics , NK Cell Lectin-Like Receptor Subfamily D/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/virology
7.
Eur J Med Res ; 26(1): 107, 2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1412355

ABSTRACT

BACKGROUND: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5). PATIENT AND METHODS: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation. RESULTS: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing. CONCLUSION: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/etiology , HLA Antigens/genetics , Receptors, CCR5/genetics , Adult , Aged , COVID-19/epidemiology , COVID-19/genetics , Female , Genetic Predisposition to Disease , Genotype , HLA-DRB1 Chains/genetics , Histocompatibility Antigens Class I/genetics , Humans , Immunoglobulin G/blood , Male , Middle Aged , Morbidity , Mutation , Severity of Illness Index
8.
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
9.
Front Immunol ; 11: 605688, 2020.
Article in English | MEDLINE | ID: covidwho-1389170

ABSTRACT

Aim: SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome. Method and Materials: We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies. Results: Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0-0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8-8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR > 2.5 (95% CI 2.7-220.6), Pc = 0.024]. Conclusion: The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease.


Subject(s)
COVID-19 , Gene Frequency , Genetic Predisposition to Disease , HLA-DRB1 Chains , Histocompatibility Antigens Class I , SARS-CoV-2/immunology , Adult , Aged , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Female , HLA-DRB1 Chains/genetics , HLA-DRB1 Chains/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immunogenetics , Italy , Male , Middle Aged , Severity of Illness Index
10.
Front Immunol ; 12: 698193, 2021.
Article in English | MEDLINE | ID: covidwho-1354865

ABSTRACT

HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the HLA genotype on the severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of in silico predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the HLA genotype.


Subject(s)
Coronavirus Infections/genetics , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class I/immunology , Adult , Computer Simulation , Cross-Sectional Studies , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Female , Genotype , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class II/genetics , Humans , Male , Middle Aged , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
11.
J Clin Pathol ; 74(8): 528-532, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1318062

ABSTRACT

AIMS: Brazil is nowadays one of the epicentres of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and new therapies are needed to face it. In the context of specific immune response against the virus, a correlation between Major Histocompatibility Complex Class I (MHC-I) and the severity of the disease in patients with COVID-19 has been suggested. Aiming at better understanding the biology of the infection and the immune response against the virus in the Brazilian population, we analysed SARS-CoV-2 protein S peptides in order to identify epitopes able to elicit an immune response mediated by the most frequent MHC-I alleles using in silico methods. METHODS: Our analyses consisted in searching for the most frequent Human Leukocyte Antigen (HLA)-A, HLA-B and HLA-C alleles in the Brazilian population, excluding the genetic isolates; then, we performed: molecular modelling for unsolved structures, MHC-I binding affinity and antigenicity prediction, peptide docking and molecular dynamics of the best fitted MHC-I/protein S complexes. RESULTS: We identified 24 immunogenic epitopes in the SARS-CoV-2 protein S that could interact with 17 different MHC-I alleles (namely, HLA-A*01:01; HLA-A*02:01; HLA-A*11:01; HLA-A*24:02; HLA-A*68:01; HLA-A*23:01; HLA-A*26:01; HLA-A*30:02; HLA-A*31:01; HLA-B*07:02; HLA-B*51:01; HLA-B*35:01; HLA-B*44:02; HLA-B*35:03; HLA-C*05:01; HLA-C*07:01 and HLA-C*15:02) in the Brazilian population. CONCLUSIONS: Being aware of the intrinsic limitations of in silico analysis (mainly the differences between the real and the Protein Data Bank (PDB) structure; and accuracy of the methods for simulate proteasome cleavage), we identified 24 epitopes able to interact with 17 MHC-I more frequent alleles in the Brazilian population that could be useful for the development of strategic methods for vaccines against SARS-CoV-2.


Subject(s)
Epitope Mapping , Epitopes , HLA Antigens/immunology , Histocompatibility Antigens Class I/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Brazil , Gene Frequency , HLA Antigens/genetics , Histocompatibility Antigens Class I/genetics , Host-Pathogen Interactions , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , SARS-CoV-2/pathogenicity
12.
Viruses ; 13(7)2021 06 27.
Article in English | MEDLINE | ID: covidwho-1289026

ABSTRACT

Many viruses, especially RNA viruses, utilize programmed ribosomal frameshifting and/or stop codon readthrough in their expression, and in the decoding of a few a UGA is dynamically redefined to specify selenocysteine. This recoding can effectively increase viral coding capacity and generate a set ratio of products with the same N-terminal domain(s) but different C-terminal domains. Recoding can also be regulatory or generate a product with the non-universal 21st directly encoded amino acid. Selection for translation speed in the expression of many viruses at the expense of fidelity creates host immune defensive opportunities. In contrast to host opportunism, certain viruses, including some persistent viruses, utilize recoding or adventitious frameshifting as part of their strategy to evade an immune response or specific drugs. Several instances of recoding in small intensively studied viruses escaped detection for many years and their identification resolved dilemmas. The fundamental importance of ribosome ratcheting is consistent with the initial strong view of invariant triplet decoding which however did not foresee the possibility of transitory anticodon:codon dissociation. Deep level dynamics and structural understanding of recoding is underway, and a high level structure relevant to the frameshifting required for expression of the SARS CoV-2 genome has just been determined.


Subject(s)
DNA Viruses/genetics , DNA Viruses/immunology , Histocompatibility Antigens Class I/immunology , Immune Evasion , RNA Viruses/genetics , Antiviral Agents/pharmacology , Codon, Terminator , DNA Viruses/drug effects , Frameshifting, Ribosomal , Histocompatibility Antigens Class I/genetics , Nucleic Acid Conformation , Peptides/immunology , Protein Biosynthesis , RNA Viruses/drug effects , RNA Viruses/immunology
13.
Proc Natl Acad Sci U S A ; 118(23)2021 06 08.
Article in English | MEDLINE | ID: covidwho-1238060

ABSTRACT

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic and has claimed over 2 million lives worldwide. Although the genetic sequences of SARS-CoV and SARS-CoV-2 have high homology, the clinical and pathological characteristics of COVID-19 differ significantly from those of SARS. How and whether SARS-CoV-2 evades (cellular) immune surveillance requires further elucidation. In this study, we show that SARS-CoV-2 infection leads to major histocompability complex class Ι (MHC-Ι) down-regulation both in vitro and in vivo. The viral protein encoded by open reading frame 8 (ORF8) of SARS-CoV-2, which shares the least homology with SARS-CoV among all viral proteins, directly interacts with MHC-Ι molecules and mediates their down-regulation. In ORF8-expressing cells, MHC-Ι molecules are selectively targeted for lysosomal degradation via autophagy. Thus, SARS-CoV-2-infected cells are much less sensitive to lysis by cytotoxic T lymphocytes. Because ORF8 protein impairs the antigen presentation system, inhibition of ORF8 could be a strategy to improve immune surveillance.


Subject(s)
Antigen Presentation , COVID-19/immunology , Down-Regulation/immunology , Histocompatibility Antigens Class I/immunology , Immune Evasion , SARS-CoV-2/immunology , Viral Proteins/immunology , Animals , Autophagy/genetics , Autophagy/immunology , COVID-19/genetics , Chlorocebus aethiops , HEK293 Cells , Histocompatibility Antigens Class I/genetics , Humans , Lysosomes/genetics , Lysosomes/immunology , Lysosomes/virology , Mice , Mice, Transgenic , SARS-CoV-2/genetics , Vero Cells , Viral Proteins/genetics
14.
Nat Commun ; 12(1): 2593, 2021 05 10.
Article in English | MEDLINE | ID: covidwho-1223090

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8+ T cells. Here, we analyze samples from 31 patients with COVID-19 for CD8+ T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8+ T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8+ T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8+ T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8+ T cells during convalescence.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Immunodominant Epitopes/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Alleles , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Epitopes, T-Lymphocyte/immunology , Female , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Immunodominant Epitopes/chemistry , Immunologic Memory , Lymphocyte Activation , Male , Middle Aged , Polyproteins/immunology , Viral Proteins/immunology
15.
J Med Virol ; 93(9): 5350-5357, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1206838

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
16.
Vet Microbiol ; 242: 108569, 2020 Mar.
Article in English | MEDLINE | ID: covidwho-1207086

ABSTRACT

In the present study, we analyzed the immune response of calves to Brucella abortus strain 19 vaccine (S19) and its association with MHC class I (BoLA-A) alleles (exons 2-3 and 4-5). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for typing of BoLA-A exon 2-3 with DdeI and TaqI restriction enzymes; and exon 4-5 with HinfI in 45 crossbred calves. The PCR-RFLP analysis revealed five BoLA-A alleles each for exon 2-3 (A10/A19, A19, A18/19, A18 and A31) and exon 4-5 (A, B, C, D and E). Immune response against B. abortus S19 was assessed at the 4th week post vaccination; antibody response by standard tube agglutination test (STAT) and cell-mediated immunity by lymphocyte proliferation and lymphocyte-mediated cytotoxicity assays. Further, the macrophage function in terms of nitrite production was also analyzed. The association analysis of various BoLA-A alleles with the elicitation of immune response revealed that calves with certain defined genotypes induced significantly higher cell-mediated immune response in terms of lymphocyte proliferation with higher stimulation indices (S.I.) of 1.59 (BoLA-A19), 1.49 (A18/19) and 1.52 (HinfI-D); lymphocyte mediated cytotoxicity (55.52 % in A19) and nitrite production (43.40 µM in A31). It is assumed that allelic variants of BoLA-A (exons 2-3 and 4-5) were associated with the differential immune response of calves to B. abortus S19 vaccination. Therefore, further studies on association analysis of MHC class-I genes in large number of cattle may generate more information and might be useful for adapting the alternative approach of exploring genetic resistance in the cattle herd against bovine brucellosis.


Subject(s)
Brucellosis, Bovine/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Immunity, Cellular , Age Factors , Alleles , Animals , Brucella Vaccine/administration & dosage , Brucella abortus/genetics , Brucellosis, Bovine/genetics , Cattle/immunology , Cattle/microbiology , Genetic Association Studies , Genetic Variation , Genotype , Lymphocyte Activation , Nitrites/metabolism
17.
J Clin Invest ; 131(10)2021 05 17.
Article in English | MEDLINE | ID: covidwho-1133410

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different Vß chains results in Vß skewing, whereby T cells with specific Vß chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCRß variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV11-2 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the Vß chain encoded by TRBV11-2 (Vß21.3) strongly interact with the superantigen-like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C.


Subject(s)
COVID-19/immunology , Complementarity Determining Regions/immunology , Histocompatibility Antigens Class I/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , COVID-19/genetics , Child , Complementarity Determining Regions/genetics , Female , Histocompatibility Antigens Class I/genetics , Humans , Male , Receptors, Antigen, T-Cell, alpha-beta/genetics , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Systemic Inflammatory Response Syndrome/genetics
18.
Int J Mol Sci ; 22(5)2021 Mar 05.
Article in English | MEDLINE | ID: covidwho-1129735

ABSTRACT

We observed substantial differences in predicted Major Histocompatibility Complex II (MHCII) epitope presentation of SARS-CoV-2 proteins for different populations but only minor differences in predicted MHCI epitope presentation. A comparison of this predicted epitope MHC-coverage revealed for the early phase of infection spread (till day 15 after reaching 128 observed infection cases) highly significant negative correlations with the case fatality rate. Specifically, this was observed in different populations for MHC class II presentation of the viral spike protein (p-value: 0.0733 for linear regression), the envelope protein (p-value: 0.023), and the membrane protein (p-value: 0.00053), indicating that the high case fatality rates of COVID-19 observed in some countries seem to be related with poor MHC class II presentation and hence weak adaptive immune response against these viral envelope proteins. Our results highlight the general importance of the SARS-CoV-2 structural proteins in immunological control in early infection spread looking at a global census in various countries and taking case fatality rate into account. Other factors such as health system and control measures become more important after the early spread. Our study should encourage further studies on MHCII alleles as potential risk factors in COVID-19 including assessment of local populations and specific allele distributions.


Subject(s)
COVID-19/mortality , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , SARS-CoV-2/chemistry , Viral Structural Proteins/chemistry , Adaptive Immunity , Alleles , COVID-19/immunology , COVID-19/transmission , Computational Biology/methods , Correlation of Data , Epitopes, B-Lymphocyte/genetics , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , HLA Antigens/genetics , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Humans , Mortality , SARS-CoV-2/immunology , Viral Structural Proteins/immunology
19.
Cell Rep Med ; 2(3): 100221, 2021 03 16.
Article in English | MEDLINE | ID: covidwho-1101542

ABSTRACT

Polymorphisms in MHC-I protein sequences across human populations significantly affect viral peptide binding capacity, and thus alter T cell immunity to infection. In the present study, we assess the relationship between observed SARS-CoV-2 population mortality and the predicted viral binding capacities of 52 common MHC-I alleles. Potential SARS-CoV-2 MHC-I peptides are identified using a consensus MHC-I binding and presentation prediction algorithm called EnsembleMHC. Starting with nearly 3.5 million candidates, we resolve a few hundred highly probable MHC-I peptides. By weighing individual MHC allele-specific SARS-CoV-2 binding capacity with population frequency in 23 countries, we discover a strong inverse correlation between predicted population SARS-CoV-2 peptide binding capacity and mortality rate. Our computations reveal that peptides derived from the structural proteins of the virus produce a stronger association with observed mortality rate, highlighting the importance of S, N, M, and E proteins in driving productive immune responses.


Subject(s)
COVID-19/mortality , Epitopes, T-Lymphocyte/immunology , Histocompatibility Antigens Class I/immunology , Algorithms , Alleles , CD8-Positive T-Lymphocytes/immunology , COVID-19/pathology , COVID-19/virology , Cell Line, Tumor , Epitopes, T-Lymphocyte/chemistry , Gene Frequency , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/genetics , Humans , Risk Factors , SARS-CoV-2/isolation & purification , Survival Analysis
20.
Molecules ; 25(22)2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-945885

ABSTRACT

Major histocompatibility complex class I (MHC I) plays a crucial role in the development of adaptive immune response in vertebrates. MHC molecules are cell surface protein complexes loaded with short peptides and recognized by the T-cell receptors (TCR). Peptides associated with MHC are named immunopeptidome. The MHC I immunopeptidome is produced by the proteasome degradation of intracellular proteins. The knowledge of the immunopeptidome repertoire facilitates the creation of personalized antitumor or antiviral vaccines. A huge number of publications on the immunopeptidome diversity of different human and mouse biological samples-plasma, peripheral blood mononuclear cells (PBMCs), and solid tissues, including tumors-appeared in the scientific journals in the last decade. Significant immunopeptidome identification efficiency was achieved by advances in technology: the immunoprecipitation of MHC and mass spectrometry-based approaches. Researchers optimized common strategies to isolate MHC-associated peptides for individual tasks. They published many protocols with differences in the amount and type of biological sample, amount of antibodies, type and amount of insoluble support, methods of post-fractionation and purification, and approaches to LC-MS/MS identification of immunopeptidome. These parameters have a large impact on the final repertoire of isolated immunopeptidome. In this review, we summarize and compare immunopeptidome isolation techniques with an emphasis on the results obtained.


Subject(s)
Histocompatibility Antigens Class I/metabolism , Peptides/isolation & purification , Proteome/metabolism , Proteomics , Animals , Antibodies/metabolism , Chromatography, Affinity , Histocompatibility Antigens Class I/genetics , Humans
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