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1.
Microbiol Spectr ; 9(3): e0165921, 2021 12 22.
Article in English | MEDLINE | ID: covidwho-1598527

ABSTRACT

COVID-19 vaccines are currently being administered worldwide and playing a critical role in controlling the pandemic. They have been designed to elicit neutralizing antibodies against Spike protein of the original SARS-CoV-2, and hence they are less effective against SARS-CoV-2 variants with mutated Spike than the original virus. It is possible that novel variants with abilities of enhanced transmissibility and/or immunoevasion will appear in the near future and perfectly escape from vaccine-elicited immunity. Therefore, the current vaccines may need to be improved to compensate for the viral evolution. For this purpose, it may be beneficial to take advantage of CD8+ cytotoxic T lymphocytes (CTLs). Several lines of evidence suggest the contribution of CTLs on the viral control in COVID-19, and CTLs target a wide range of proteins involving comparatively conserved nonstructural proteins. Here, we identified 22 HLA-A*24:02-restricted CTL candidate epitopes derived from the nonstructural polyprotein 1a (pp1a) of SARS-CoV-2 using computational algorithms, HLA-A*24:02 transgenic mice and the peptide-encapsulated liposomes. We focused on pp1a and HLA-A*24:02 because pp1a is relatively conserved and HLA-A*24:02 is predominant in East Asians such as Japanese. The conservation analysis revealed that the amino acid sequences of 7 out of the 22 epitopes were hardly affected by a number of mutations in the Sequence Read Archive database of SARS-CoV-2 variants. The information of such conserved epitopes might be useful for designing the next-generation COVID-19 vaccine that is universally effective against any SARS-CoV-2 variants by the induction of both anti-Spike neutralizing antibodies and CTLs specific for conserved epitopes. IMPORTANCE COVID-19 vaccines have been designed to elicit neutralizing antibodies against the Spike protein of the original SARS-CoV-2, and hence they are less effective against variants. It is possible that novel variants will appear and escape from vaccine-elicited immunity. Therefore, the current vaccines may need to be improved to compensate for the viral evolution. For this purpose, it may be beneficial to take advantage of CD8+ cytotoxic T lymphocytes (CTLs). Here, we identified 22 HLA-A*24:02-restricted CTL candidate epitopes derived from the nonstructural polyprotein 1a (pp1a) of SARS-CoV-2. We focused on pp1a and HLA-A*24:02 because pp1a is conserved and HLA-A*24:02 is predominant in East Asians. The conservation analysis revealed that the amino acid sequences of 7 out of the 22 epitopes were hardly affected by mutations in the database of SARS-CoV-2 variants. The information might be useful for designing the next-generation COVID-19 vaccine that is universally effective against any variants.


Subject(s)
COVID-19/immunology , Epitopes/immunology , HLA-A24 Antigen/genetics , HLA-A24 Antigen/immunology , Mutation , Polyproteins/genetics , SARS-CoV-2/genetics , T-Lymphocytes, Cytotoxic/immunology , Amino Acid Sequence , Animals , Antibodies, Neutralizing/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/immunology , Epitopes/genetics , HLA-A24 Antigen/isolation & purification , Humans , Mice , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology
2.
Biomolecules ; 11(7)2021 07 19.
Article in English | MEDLINE | ID: covidwho-1328091

ABSTRACT

Proteins of the major histocompatibility complex (MHC) class I, or human leukocyte antigen (HLA) in humans interact with endogenous peptides and present them to T cell receptors (TCR), which in turn tune the immune system to recognize and discriminate between self and foreign (non-self) peptides. Of especial importance are peptides derived from tumor-associated antigens. T cells recognizing these peptides are found in cancer patients, but not in cancer-free individuals. What stimulates this recognition, which is vital for the success of checkpoint based therapy? A peptide derived from the protein p53 (residues 161-169 or p161) was reported to show this behavior. T cells recognizing this unmodified peptide could be further stimulated in vitro to create effective cancer killing CTLs (cytotoxic T lymphocytes). We hypothesize that the underlying difference may arise from post-translational glycosylation of p161 in normal individuals, likely masking it against recognition by TCR. Defects in glycosylation in cancer cells may allow the presentation of the native peptide. We investigate the structural consequences of such peptide glycosylation by investigating the associated structural dynamics.


Subject(s)
HLA-A24 Antigen/chemistry , HLA-A24 Antigen/metabolism , Receptors, Antigen, T-Cell/metabolism , Tumor Suppressor Protein p53/metabolism , Acetylglucosamine/metabolism , Glycosylation , Human Immunodeficiency Virus Proteins/chemistry , Human Immunodeficiency Virus Proteins/metabolism , Humans , Hydrogen Bonding , Models, Molecular , Molecular Dynamics Simulation , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Protein Conformation , Receptors, Antigen, T-Cell/chemistry , Tumor Suppressor Protein p53/chemistry
3.
Acta Trop ; 221: 106013, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1272275

ABSTRACT

AIM: This study is looking for a common pathogenicity between SARS-CoV-2 and Plasmodium species, in individuals with certain HLA serotypes. METHODS: 1. Tblastx searches of SARS-CoV-2 are performed by limiting searches to five Plasmodium species that infect humans. 2. Aligned sequences in the respective organisms' proteomes are searched with blastp. 3. Binding predictions of the identified SARS-CoV-2 peptide to HLA supertype representatives are performed. 4. Blastp searches of predicted epitopes that bind strongly to the identified HLA allele are performed by limiting searches to H. sapiens and Plasmodium species, separately. 5. Peptides with minimum 60% identity to the predicted epitopes are found in results. 6. Peptides among those, which bind strongly to the same HLA allele, are predicted. 7. Step-4 is repeated by limiting searches to H. sapiens, followed by the remaining steps until step-7, for peptides sourced by Plasmodium species after step-6. RESULTS: SARS-CoV-2 peptide with single letter amino acid code CFLGYFCTCYFGLFC has the highest identity to P. vivax. Its YFCTCYFGLF part is predicted to bind strongly to HLA-A*24:02. Peptides in the human proteome both homologous to YFCTCYFGLF and with a strong binding affinity to HLA-A*24:02 are YYCARRFGLF, YYCHCPFGVF, and YYCQQYFFLF. Such peptides in the Plasmodium species' proteomes are FFYTFYFELF, YFVACLFILF, and YFPTITFHLF. The first one belonging to P. falciparum has a homologous peptide (YFYLFSLELF) in the human proteome, which also has a strong binding affinity to the same HLA allele. CONCLUSION: Immune responses to the identified-peptides with similar sequences and strong binding affinities to HLA-A*24:02 can be related to autoimmune response risk in individuals with HLA-A*24:02 serotypes, upon getting infected with SARS-CoV-2 or P. falciparum.


Subject(s)
COVID-19 , HLA-A24 Antigen , Malaria, Vivax , Peptides , Epitopes, T-Lymphocyte , Humans , Peptides/genetics , SARS-CoV-2
4.
Immunol Cell Biol ; 99(9): 990-1000, 2021 10.
Article in English | MEDLINE | ID: covidwho-1258941

ABSTRACT

In-depth understanding of human T-cell-mediated immunity in coronavirus disease 2019 (COVID-19) is needed if we are to optimize vaccine strategies and immunotherapies. Identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell epitopes and generation of peptide-human leukocyte antigen (peptide-HLA) tetramers facilitate direct ex vivo analyses of SARS-CoV-2-specific T cells and their T-cell receptor (TCR) repertoires. We utilized a combination of peptide prediction and in vitro peptide stimulation to validate novel SARS-CoV-2 epitopes restricted by HLA-A*24:02, one of the most prominent HLA class I alleles, especially in Indigenous and Asian populations. Of the peptides screened, three spike-derived peptides generated CD8+ IFNγ+ responses above background, S1208-1216 (QYIKWPWYI), S448-456 (NYNYLYRLF) and S193-201 (VFKNIDGYF), with S1208 generating immunodominant CD8+ IFNγ+ responses. Using peptide-HLA-I tetramers, we performed direct ex vivo tetramer enrichment for HLA-A*24:02-restricted CD8+ T cells in COVID-19 patients and prepandemic controls. The precursor frequencies for HLA-A*24:02-restricted epitopes were within the range previously observed for other SARS-CoV-2 epitopes for both COVID-19 patients and prepandemic individuals. Naïve A24/SARS-CoV-2-specific CD8+ T cells increased nearly 7.5-fold above the average precursor frequency during COVID-19, gaining effector and memory phenotypes. Ex vivo single-cell analyses of TCRαß repertoires found that the A24/S448 + CD8+ T-cell TCRαß repertoire was driven by a common TCRß chain motif, whereas the A24/S1208 + CD8+ TCRαß repertoire was diverse across COVID-19 patients. Our study provides an in depth characterization and important insights into SARS-CoV-2-specific CD8+ T-cell responses associated with a prominent HLA-A*24:02 allomorph. This contributes to our knowledge on adaptive immune responses during primary COVID-19 and could be exploited in vaccine or immunotherapeutic approaches.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19 , HLA-A24 Antigen , Receptors, Antigen, T-Cell/immunology , COVID-19/immunology , Humans , SARS-CoV-2
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