Single-cell RNA sequencing of blood antigen-presenting cells in severe Covid-19 reveals multi-process defects in antiviral immunity

Saichi, Melissa; Ladjemi, Maha Zohra; Korniotis, Sarantis; Rousseau, C.; Ait-Hamou, Zakaria; Massenet, Lucile; Amblard, Elise; Noël, Floriane; Marie, Yannick; Bouteiller, Delphine; Medvedovic, Jasna; Pène, Frédéric; Soumelis, Vassili

doi:10.1183/13993003.congress-2021.oa4309

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“…As SARS-CoV-2 infects pAPCs including DCs, macrophages, and B cells-as well as non-professional APCs in the lung-this suppression of MHC II has the potential to dramatically decrease the activation of CD4 + T cells in COVID-19 patients [6][7][8]. Such a loss of CD4 + T cell activity likely contributes to the shorter-lived humoral immunity and propensity for reinfection of COVID-19 patients, and may contribute to the aberrant formation of memory and effector CD4 + T cell subsets in patients with severe disease [24,[69][70][71][72].…”

Section: Discussionmentioning

confidence: 99%

“…MHC I is further suppressed by ORF6, which inactivates CITA/NLRC5-the master regulator of MHC I expression [23]. Finally, infection of alveolar DCs reduces their ability to migrate to draining lymph nodes and suppresses expression of MHC class II and the class II transcriptional activator (CIITA) required for MHC II expression [24]. This suppression of MHC II occurs across a range of pAPCs in SARS-CoV-2 infected patients and in cells infected in-vitro [25][26][27].…”

Section: Introductionmentioning

confidence: 99%

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SARS-COV-2 NSP5 Antagonizes MHC II Expresion by Subverting Histone Deacetylase 2

Taefehshokr

Lac

Vrieze

et al. 2023

Preprint

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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.

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