Dataset Information

Mutations in epitope flanking regions for SARS-CoV-2 nucleoprotein affect proteasomal processing to alter CD8+ T cell responses

ABSTRACT: Viral CD8+ epitopes are generated by the cellular turnover of viral proteins, predominantly by the proteasome1. Mutations located within viral epitopes can result in escape from memory T cells2. Focussing on two of the most dominant SARS-CoV-2 nucleoprotein CD8+ epitopes3,4, we identified mutations in epitope flanking regions. Using SARS-CoV-2 nucleoprotein transduced B cell lines and in vitro proteasomal processing of peptides, we investigated the contribution of these mutations to antigen processing and T cell activation. We found that decreased NP9-17-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 and suggesting an immune escape caused by this mutation. In contrast, NP-P6L and NP-D103N/Y mutations flanking the NP9-17-B*27:05 and NP105-113-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 significant impact on antigen processing and presentation, thereby contributing to escape from immunodominant T cell responses. Alternatively, mutations could enhance antigen processing and T cell efficacy, opening new avenues for improving future vaccine designs.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Recombinant Sars Coronavirus

DISEASE(S): Covid-19

SUBMITTER: Zhanru Yu

LAB HEAD: Roman Fischer

PROVIDER: PXD032054 | Pride | 2023-10-24

REPOSITORIES: Pride

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Publications

SARS-CoV-2 mutations affect antigen processing by the proteasome to alter CD8+ T cell responses.

Wellington Dannielle D Yin Zixi Z Yu Zhanru Z Heilig Raphael R Davis Simon S Fischer Roman R Felce Suet Ling SL Antoun Elie E Hublitz Philip P Beveridge Ryan R Dong Danning D Liu Guihai G Yao Xuan X Peng Yanchun Y Kessler Benedikt M BM Dong Tao T

Heliyon 20230914 10

Mutations within viral epitopes can result in escape from T cells, but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two SARS-CoV-2 nucleoprotein CD8+ epitopes, we investigated the contribution of these flanking mutations to proteasomal processing and T cell activation. We found decreased NP9-17-B*27:05 CD8+ T cell responses to the NP-Q7K mutation, likely due to a lack of efficient epitope produ ...[more]

PMID: 37842619

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Project description:Sanjuan2013 - Evolution of HIV T-cell epitope, control model Control model in which the virus targets a nonimmune cell type C (e.g., hepatocytes, epithelial cells, etc.), instead of T H cells. This model is described in the article: Immune activation promotes evolutionary conservation of T-cell epitopes in HIV-1. Sanjuán R, Nebot MR, Peris JB, Alcamí J. PLoS Biol. 2013 Apr;11(4):e1001523 Abstract: The immune system should constitute a strong selective pressure promoting viral genetic diversity and evolution. However, HIV shows lower sequence variability at T-cell epitopes than elsewhere in the genome, in contrast with other human RNA viruses. Here, we propose that epitope conservation is a consequence of the particular interactions established between HIV and the immune system. On one hand, epitope recognition triggers an anti-HIV response mediated by cytotoxic T-lymphocytes (CTLs), but on the other hand, activation of CD4(+) helper T lymphocytes (TH cells) promotes HIV replication. Mathematical modeling of these opposite selective forces revealed that selection at the intrapatient level can promote either T-cell epitope conservation or escape. We predict greater conservation for epitopes contributing significantly to total immune activation levels (immunodominance), and when TH cell infection is concomitant to epitope recognition (trans-infection). We suggest that HIV-driven immune activation in the lymph nodes during the chronic stage of the disease may offer a favorable scenario for epitope conservation. Our results also support the view that some pathogens draw benefits from the immune response and suggest that vaccination strategies based on conserved TH epitopes may be counterproductive. This model is hosted on BioModels Database and identified by: MODEL1302180002 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Dataset Information

Mutations in epitope flanking regions for SARS-CoV-2 nucleoprotein affect proteasomal processing to alter CD8+ T cell responses

Publications

SARS-CoV-2 mutations affect antigen processing by the proteasome to alter CD8<sup>+</sup> T cell responses.

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