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Allotypic variation in antigen processing controls antigenic peptide generation from SARS-CoV-2 S1 Spike Glycoprotein

George Stamatakis, Martina Samiotaki, Ioannis Temponeras, George Panayotou, View ORCID ProfileEfstratios Stratikos
doi: https://doi.org/10.1101/2021.07.03.450989
George Stamatakis
1Institute for Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
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Martina Samiotaki
1Institute for Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
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Ioannis Temponeras
2National Centre for Scientific Research “Demokritos”, 15310 Agia Paraskevi, Attica, Greece
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George Panayotou
1Institute for Bioinnovation, Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Attica, Greece
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Efstratios Stratikos
2National Centre for Scientific Research “Demokritos”, 15310 Agia Paraskevi, Attica, Greece
3Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zographou, 15784, Athens, Greece
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  • ORCID record for Efstratios Stratikos
  • For correspondence: estratikos@chem.uoa.gr
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ABSTRACT

Population genetic variability in immune system genes can often underlie variability in immune responses to pathogens. Cytotoxic T-lymphocytes are emerging as critical determinants of both SARS-CoV-2 infection severity and long-term immunity, either after recovery or vaccination. A hallmark of COVID-19 is its highly variable severity and breadth of immune responses between individuals. To address the underlying mechanisms behind this phenomenon we analyzed the proteolytic processing of S1 spike glycoprotein precursor antigenic peptides by 10 common allotypes of ER aminopeptidase 1 (ERAP1), a polymorphic intracellular enzyme that can regulate cytotoxic T-lymphocyte responses by generating or destroying antigenic peptides. We utilized a systematic proteomic approach that allows the concurrent analysis of hundreds of trimming reactions in parallel, thus better emulating antigen processing in the cell. While all ERAP1 allotypes were capable of producing optimal ligands for MHC class I molecules, including known SARS-CoV-2 epitopes, they presented significant differences in peptide sequences produced, suggesting allotype-dependent sequence biases. Allotype 10, previously suggested to be enzymatically deficient, was rather found to be functionally distinct from other allotypes. Our findings suggest that common ERAP1 allotypes can be a major source of heterogeneity in antigen processing and through this mechanism contribute to variable immune responses to COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 04, 2021.
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Allotypic variation in antigen processing controls antigenic peptide generation from SARS-CoV-2 S1 Spike Glycoprotein
George Stamatakis, Martina Samiotaki, Ioannis Temponeras, George Panayotou, Efstratios Stratikos
bioRxiv 2021.07.03.450989; doi: https://doi.org/10.1101/2021.07.03.450989
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Allotypic variation in antigen processing controls antigenic peptide generation from SARS-CoV-2 S1 Spike Glycoprotein
George Stamatakis, Martina Samiotaki, Ioannis Temponeras, George Panayotou, Efstratios Stratikos
bioRxiv 2021.07.03.450989; doi: https://doi.org/10.1101/2021.07.03.450989

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