RESUMEN
SARS-CoV-2 interferes with antigen presentation by downregulating major histocompatibility complex (MHC) II on antigen-presenting cells, but the mechanism mediating this process is unelucidated. Herein, analysis of protein and gene expression in human antigen-presenting cells reveals that MHC II is downregulated by the SARS-CoV-2 main protease, NSP5. This suppression of MHC II expression occurs via decreased expression of the MHC II regulatory protein CIITA. CIITA downregulation is independent of the proteolytic activity of NSP5, and rather, NSP5 delivers HDAC2 to the transcription factor IRF3 at an IRF-binding site within the CIITA promoter. 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 mechanism by which SARS-CoV-2 limits MHC II expression, thereby delaying or weakening the subsequent adaptive immune response.
Asunto(s)
Antígenos de Histocompatibilidad Clase II , Histona Desacetilasa 2 , Proteínas Nucleares , Regiones Promotoras Genéticas , SARS-CoV-2 , Transactivadores , Humanos , Presentación de Antígeno/genética , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/inmunología , COVID-19/virología , COVID-19/inmunología , COVID-19/genética , COVID-19/metabolismo , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/genética , Regulación hacia Abajo/genética , Células HEK293 , Antígenos de Histocompatibilidad Clase II/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/inmunología , Transactivadores/metabolismo , Transactivadores/genética , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genéticaRESUMEN
CD11d/CD18 is the most recently discovered and least understood ß2 integrin. Known CD11d adhesive mechanisms contribute to both extravasation and mesenchymal migration - two key aspects for localizing peripheral leukocytes to sites of inflammation. Differential expression of CD11d induces differences in monocyte/macrophage mesenchymal migration including impacts on macrophage sub-set migration. The participation of CD11d/CD18 in leukocyte localization during atherosclerosis and following neurotrauma has sparked interest in the development of CD11d-targeted therapeutic agents. Whereas the adhesive properties of CD11d have undergone investigation, the signalling pathways induced by ligand binding remain largely undefined. Underlining each adhesive and signalling function, CD11d is under unique transcriptional control and expressed on a sub-set of predominately tissue-differentiated innate leukocytes. The following review is the first to capture the nearly three decades of CD11d research and discusses the emerging role of CD11d in leukocyte migration and retention during the progression of a staged immune response.