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):

ORGANISM(S): Recombinant Sars Coronavirus

DISEASE(S): Covid-19

SUBMITTER: Zhanru Yu  

LAB HEAD: Roman Fischer

PROVIDER: PXD032054 | Pride | 2023-10-24

REPOSITORIES: Pride