HLA-dependent heterogeneity and macrophage immunoproteasome activation during lung COVID-19 disease

Journal of Translational Medicine

Ali G. Turhan¹  Annelise Bennaceur-Griscelli¹  Frank Griscelli²  Christophe Desterke³ 

[1] INSERM UA9- University Paris-Saclay, 94800, Villejuif, France;ESTeam Paris Sud, INGESTEM National IPSC Infrastructure, University Paris-Saclay, 94800, Villejuif, France;Division of Hematology, Kremlin-Bicetre Hospital, 94270, Kremlin Bicetre, France;University Paris Saclay, Faculty of Medicine, 94275, Le Kremlin Bicêtre, France;INSERM UA9- University Paris-Saclay, 94800, Villejuif, France;ESTeam Paris Sud, INGESTEM National IPSC Infrastructure, University Paris-Saclay, 94800, Villejuif, France;University of Paris, Faculty Sorbonne Paris Cité, Faculté Des Sciences Pharmaceutiques Et Biologiques, Paris, France;Department of Biopathology, Gustave-Roussy Cancer Institute, 94800, Villejuif, France;INSERM UA9, Institut André Lwoff, Hôpital Paul Brousse, Bâtiment A CNRS, 7 rue Guy Moquet, 94802, Villejuif, France;INSERM UA9- University Paris-Saclay, 94800, Villejuif, France;University Paris Saclay, Faculty of Medicine, 94275, Le Kremlin Bicêtre, France;

关键词: COVID-19;    Macrophage;    Immunoproteasome;    HLA;    Peptidome;    Antigen presentation;    Transcriptome;    Integrative analysis;    MHC class-I;   

DOI  :  10.1186/s12967-021-02965-5

来源: Springer

【 摘 要 】

BackgroundThe worldwide pandemic caused by the SARS-CoV-2 virus is characterized by significant and unpredictable heterogeneity in symptoms that remains poorly understood.MethodsTranscriptome and single cell transcriptome of COVID19 lung were integrated with deeplearning analysis of MHC class I immunopeptidome against SARS-COV2 proteome.ResultsAn analysis of the transcriptomes of lung samples from COVID-19 patients revealed that activation of MHC class I antigen presentation in these tissues was correlated with the amount of SARS-CoV-2 RNA present. Similarly, a positive relationship was detected in these samples between the level of SARS-CoV-2 and the expression of a genomic cluster located in the 6p21.32 region (40 kb long, inside the MHC-II cluster) that encodes constituents of the immunoproteasome. An analysis of single-cell transcriptomes of bronchoalveolar cells highlighted the activation of the immunoproteasome in CD68 + M1 macrophages of COVID-19 patients in addition to a PSMB8-based trajectory in these cells that featured an activation of defense response during mild cases of the disease, and an impairment of alveolar clearance mechanisms during severe COVID-19. By examining the binding affinity of the SARS-CoV-2 immunopeptidome with the most common HLA-A, -B, and -C alleles worldwide, we found higher numbers of stronger presenters in type A alleles and in Asian populations, which could shed light on why this disease is now less widespread in this part of the world.ConclusionsHLA-dependent heterogeneity in macrophage immunoproteasome activation during lung COVID-19 disease could have implications for efforts to predict the response to HLA-dependent SARS-CoV-2 vaccines in the global population.

【 授权许可】

CC BY