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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-333124

ABSTRACT

Viral CD8 + epitopes are generated by the cellular turnover of viral proteins, predominantly by the proteasome. Mutations located within viral epitopes can result in escape from memory T cells but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two of the most dominant SARS-CoV-2 nucleoprotein CD8 + epitopes, we identified mutations in epitope flanking regions and investigated the contribution of these mutations to antigen processing and T cell activation using SARS-CoV-2 nucleoprotein transduced B cell lines and in vitro proteasomal processing of peptides. We found that decreased NP 9-17 -B*27:05 CD8 + T cell responses to the NP-Q7K mutation correlated with lower epitope surface expression, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103N/Y mutations flanking the NP 9-17 -B*27:05 and NP 105-113 -B*07:02 epitopes, respectively, increased CD8 + T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on antigen processing and presentation, thereby contributing to escape from immunodominant T cell responses. Alternatively, mutations could enhance antigen processing and efficacy of T cell recognition, opening new avenues for improving future vaccine designs. One Sentence Summary Natural mutations in the flanking regions of known immunodominant SARS-CoV-2 nucleoprotein epitopes can decrease CD8 + T cell responses leading to partial escape.

2.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-328783

ABSTRACT

Little is known of the role of cytotoxic CD4 + T-cells in the control of viral replication. Here, we investigate CD4 + T-cell responses to three dominant SARS-CoV-2 epitopes and evaluate antiviral activity, including cytotoxicity and antiviral cytokine production. Diverse T cell receptor (TCR) usage including public TCRs were identified;surprisingly, cytotoxic CD4 + T-cells were found to have signalling and cytotoxic pathways distinct from classical CD8 + T-cells, with increased expression of chemokines and tissue homing receptors promoting migration. We show the presence of cytolytic CD4 + T-cells during primary infection associates with COVID-19 disease severity. Robust immune memory 6-9 months post-infection or vaccination provides CD4 + T-cells with potent antiviral activity. Our data support a model where CD4 + killer cells drive immunopathogenesis during primary infection and CD4 + memory responses are protective during secondary infection. Our study highlights the unique features of cytotoxic CD4 + T-cells that use distinct functional pathways, providing preventative and therapeutic opportunities.

3.
Nat Immunol ; 23(1): 50-61, 2022 01.
Article in English | MEDLINE | ID: covidwho-1545628

ABSTRACT

NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.


Subject(s)
HLA-B7 Antigen/immunology , Immunodominant Epitopes/immunology , Nucleocapsid Proteins/immunology , SARS-CoV-2/immunology , T-Lymphocytes, Cytotoxic/immunology , Aged , Amino Acid Sequence , Antibodies, Viral/immunology , Antibody Affinity/immunology , COVID-19/immunology , COVID-19/pathology , Cell Line, Transformed , Female , Gene Expression Profiling , Humans , Immunologic Memory/immunology , Male , Middle Aged , Receptors, Antigen, T-Cell/immunology , Severity of Illness Index , Vaccinia virus/genetics , Vaccinia virus/immunology , Vaccinia virus/metabolism
4.
iScience ; 24(11): 103353, 2021 Nov 19.
Article in English | MEDLINE | ID: covidwho-1509904

ABSTRACT

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

5.
The American Journal of Gastroenterology ; 116, 2021.
Article in English | ProQuest Central | ID: covidwho-1478570

ABSTRACT

Endpoints presented here are the percentage of patients in clinical remission at wk 8, per Adapted Mayo score, and the percentage of patients with a clinical response at wk 2, per partial Adapted Mayo score (both defined in Table footnotes), respectively, in patients who were on concomitant CS at baseline, at a dose maintained to the end of induction and in those treated with UPA without concomitant CS. Similar results were found with the clinical response rate at wk 2, with no difference between UPA-treated patients who received baseline CS (U-ACHIEVE: 58.1%;U-ACCOMPLISH: 55.1%) and those that received UPA without CS (U-ACHIEVE: 61.4%;U-ACCOMPLISH: 67.7%). Subjects were considered "non-responder" for binary endpoints at and after the UC-related corticosteroids censoring time point through the end of the Induction Study. † Dosing for main corticosteroids were as follows: prednisone. 10-40 mg QD, budesonide, 9 mg QD;or beclomethasone, 5 mg QD. § 95% CI for response rate is the synthetic result based on Student's t-distribution from PROC MIANALYZE procedure if there were missing data due to COVID-19 or is based on the normal approximation to the binomial distribution if there are no missing data due to COVID-19. ‡ 95% CI for response rate difference was calculated based on normal approximation to the binomial distribution.

6.
Microb Pathog ; 150: 104706, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-988886

ABSTRACT

To explore the applicability of MuLBSTA Score in COVID-19 patients, a retrospective analysis was performed on 330 cases of COVID-19 patients in Southeast Hospital of Xiaogan City, Hubei Province. The clinical characteristics of COVID-19 patients were described and multilobe infiltrate in CT, bacterial infection, lymphocyte count, smoke in history, history of hypertension, and age distribution in the population of mild and severe patients were analyzed. All included patients were scored according to the MuLBSTA early warning scoring system and its efficacy in early warning of severe symptoms was analyzed. CT feature of infiltration changes on multiple lobes, the absolute value of lymphocyte count of less than 0.8 × 109, accompanied by bacterial infection, history of smoking, history of hypertension, and an age of greater than 60 years old were all statistically significant factors in patients with severe COVID-19. ROC curve analysis indicated that the sensitivity, specificity and accuracy of the early warning system were 0.651, 0.954 and 0.93, respectively. The MuLBSTA Score has a good early warning effect on severe COVID-19 patients.


Subject(s)
COVID-19/diagnosis , Adult , Aged , Aged, 80 and over , Bacterial Infections/virology , COVID-19/epidemiology , COVID-19/microbiology , COVID-19 Testing , China/epidemiology , Female , Humans , Lymphocyte Count , Male , Middle Aged , Prognosis , ROC Curve , Retrospective Studies , SARS-CoV-2/isolation & purification , Smoking
7.
Nat Immunol ; 21(11): 1336-1345, 2020 11.
Article in English | MEDLINE | ID: covidwho-889210

ABSTRACT

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.


Subject(s)
Antigens, Viral/immunology , Betacoronavirus/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/prevention & control , Epitopes, T-Lymphocyte/immunology , Humans , Immunodominant Epitopes/immunology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , United Kingdom , Viral Vaccines/immunology
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