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

Abstract

Background The worldwide pandemic caused by the SARS-CoV-2 virus is characterized by significant and unpredictable heterogeneity in symptoms that remains poorly understood. Methods Transcriptome and single cell transcriptome of COVID19 lung were integrated with deeplearning analysis of MHC class I immunopeptidome against SARS-COV2 proteome. Results An 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. Conclusions HLA-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.

The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy

“…Meanwhile, in previous clinical trials, a decrease in the expression of PPAR subtypes and an increase in the serum level of proinflammatory cytokines have been observed in inflammatory lungs of patients with severe COVID-19 (112,113,140). Additionally, in agreement with the results of clinical studies, several recent transcriptomics studies using microarray, RNA-sequencing (RNA-seq), and singlecell RNA-seq techniques have reported downregulation of PPARs in various tissues including whole blood, lung epithelial cells, bronchoalveolar lavage fluids (BALFs), and peripheral blood mononuclear cells (PBMCs) in the SARS-CoV-2-infected individuals (141)(142)(143)(144)(145). Following these findings, the results of previous proteomics and metabolomics studies also indicate the interference of SARS-CoV-2 infection in PPAR signaling (146,147).…”

On the Role of the Immunoproteasome in Protein Homeostasis

“…The involvement of the immunoproteasome in antigen processing influences the pathogen-induced cytotoxic T lymphocyte (CTL) responses, pathogen clearance, and shapes the CTL repertoire [5][6][7][8][9][10]. Apart from MHC-I antigen processing, immunoproteasomes are involved in T cell expansion [7,11,12], T helper cell differentiation [13,14], macrophage polarisation [15,16], in protection from immunopathological damage in the brain [17,18], lung-associated diseases [19][20][21][22], neurodegenerative diseases [23][24][25][26][27][28][29][30][31], and inflammatory diseases [14,[32][33][34][35][36][37][38][39] (summarized in [40]). A specific role of the immunoproteasome in NF-κB activation has remained controversial [41][42][43][44][45].…”

MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil

“…These associations involve TAP1 and TAP2 , which participate in the peptide pumping from the cytoplasm to the endoplasmic reticulum, and gene HLA-A , which will present these peptides on the cell surface to T CD8 lymphocytes ( Tables 1 , 2 ). High expression levels of TAP1 and TAP2 are correlated with the amount of virus in lung tissue ( 70 ). The TAP2 signal might be a hitchhiking association due to linkage with HLA-DOB*01:02 ( Figure S7 ).…”

“…The higher frequency of 62R-63N in the SEVERE group is related to alleles A*33:03, A*68:01, and A*68:02. A*68 alleles are among the strong binders for SARs-CoV-2 peptides ( 78 , 79 ) and among the best binders for respiratory viruses ( 70 ).…”