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SARS-CoV-2 NSP5 Antagonizes the MHC II Antigen Presentation Pathway by Hijacking Histone Deacetylase 2

Nima Taefehshokr, Alex Lac, Angela M Vrieze, Brandon H Dickson, Peter N Guo, Catherine Jung, Eoin N Blythe, Corby Fink, Gregory A Dekaban, View ORCID ProfileBryan Heit
doi: https://doi.org/10.1101/2023.02.10.528032
Nima Taefehshokr
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
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Alex Lac
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
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Angela M Vrieze
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
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Brandon H Dickson
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
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Peter N Guo
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
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Catherine Jung
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
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Eoin N Blythe
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
2Robarts Research Institute, London, Ontario, Canada, N6A 3K7
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Corby Fink
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
2Robarts Research Institute, London, Ontario, Canada, N6A 3K7
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Gregory A Dekaban
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
2Robarts Research Institute, London, Ontario, Canada, N6A 3K7
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Bryan Heit
1Department of Microbiology and Immunology, and the Western Infection, Immunity and Inflammation Centre, The University of Western Ontario, London, Ontario, Canada, N6A 5C1
2Robarts Research Institute, London, Ontario, Canada, N6A 3K7
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  • ORCID record for Bryan Heit
  • For correspondence: bheit@uwo.ca
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Abstract

The clearance of SARS-CoV-2 requires a multi-faceted immune response that is initiated by innate immune cells, with infection ultimately resolved by adaptive immune mechanisms. Induction of adaptive immunity to SARS-CoV-2 is dependent on the presentation of viral antigens on MHC II by professional antigen presenting cells such as dendritic cells and macrophages, to induce robust activation of CD4+ T cells. SARS-CoV-2 interferes with antigen presentation by downregulating MHC II on the antigen presenting cells of COVID-19 patients, but the molecular mechanism mediating this process is unelucidated. In this study, analysis of protein and gene expression in human antigen presenting cells reveals that the expression of MHC II is inhibited by the SARS-CoV-2 main protease, NSP5. Suppression of MHC II expression occurs via downregulation of the transcription factor CIITA, which is required for MHC II expression. This downregulation of CIITA is independent of NSP5’s proteolytic activity, and rather, NSP5 delivers HDAC2 to the CIITA promoter via interactions with IRF3, Here, HDAC2 deacetylates and inactivates the CIITA promoter. This loss of CIITA expression prevents further expression of MHC II, with this suppression alleviated by ectopic expression of CIITA or knockdown of HDAC2. These results identify a novel mechanism by which SARS-CoV-2 can limit antigen presentation on MHC II, thereby delaying or weakening the subsequent adaptive immune response.

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 4.0 International license.
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Posted February 10, 2023.
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SARS-CoV-2 NSP5 Antagonizes the MHC II Antigen Presentation Pathway by Hijacking Histone Deacetylase 2
Nima Taefehshokr, Alex Lac, Angela M Vrieze, Brandon H Dickson, Peter N Guo, Catherine Jung, Eoin N Blythe, Corby Fink, Gregory A Dekaban, Bryan Heit
bioRxiv 2023.02.10.528032; doi: https://doi.org/10.1101/2023.02.10.528032
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SARS-CoV-2 NSP5 Antagonizes the MHC II Antigen Presentation Pathway by Hijacking Histone Deacetylase 2
Nima Taefehshokr, Alex Lac, Angela M Vrieze, Brandon H Dickson, Peter N Guo, Catherine Jung, Eoin N Blythe, Corby Fink, Gregory A Dekaban, Bryan Heit
bioRxiv 2023.02.10.528032; doi: https://doi.org/10.1101/2023.02.10.528032

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