Differential haplotype expression in class I MHC genes during SARS-CoV-2 infection of human lung cell lines

Abstract

IntroductionCell entry of SARS-CoV-2 causes genome-wide disruption of the transcriptional profiles of genes and biological pathways involved in the pathogenesis of COVID-19. Expression allelic imbalance is characterized by a deviation from the Mendelian expected 1:1 expression ratio and is an important source of allele-specific heterogeneity. Expression allelic imbalance can be measured by allele-specific expression analysis (ASE) across heterozygous informative expressed single nucleotide variants (eSNVs). ASE reflects many regulatory biological phenomena that can be assessed by combining genome and transcriptome information. ASE contributes to the interindividual variability associated with the disease. We aim to estimate the transcriptome-wide impact of SARS-CoV-2 infection by analyzing eSNVs.MethodsWe compared ASE profiles in the human lung cell lines Calu-3, A459, and H522 before and after infection with SARS-CoV-2 using RNA-Seq experiments.ResultsWe identified 34 differential ASE (DASE) sites in 13 genes (HLA-A, HLA-B, HLA-C, BRD2, EHD2, GFM2, GSPT1, HAVCR1, MAT2A, NQO2, SUPT6H, TNFRSF11A, UMPS), all of which are enriched in protein binding functions and play a role in COVID-19. Most DASE sites were assigned to the MHC class I locus and were predominantly upregulated upon infection. DASE sites in the MHC class I locus also occur in iPSC-derived airway epithelium basal cells infected with SARS-CoV-2. Using an RNA-Seq haplotype reconstruction approach, we found DASE sites and adjacent eSNVs in phase (i.e., predicted on the same DNA strand), demonstrating differential haplotype expression upon infection. We found a bias towards the expression of the HLA alleles with a higher binding affinity to SARS-CoV-2 epitopes.DiscussionIndependent of gene expression compensation, SARS-CoV-2 infection of human lung cell lines induces transcriptional allelic switching at the MHC loci. This suggests a response mechanism to SARS-CoV-2 infection that swaps HLA alleles with poor epitope binding affinity, an expectation supported by publicly available proteome data.

Integrated Immunopeptidomics and Proteomics Study of SARS-CoV-2–Infected Calu-3 Cells Reveals Dynamic Changes in Allele-specific HLA Abundance and Antigen Presentation

“…S12 ). These results were consistent with recent studies that analyzed the allele-specific abundance change of HLAs from Calu-3 cells during SARS-CoV-2 infection by transcriptomics and HLA genotyping from multiple independent studies ( 47 , 48 ). Interestingly, the abundance changes of C∗:07 glycopeptides showed different patterns compared with that from C∗:15 glycopeptides as there were no significant increase of either mono-glucosylated glycopeptide or glycopeptides with fewer than five mannoses ( Fig.…”

“…The result from this integrated study might be able to explain the imbalanced innate and adaptive immune response of SARS-CoV-2 infection, which was not reported in other similar proteomics study with different cell lines. However, the imbalanced allele–specific transcription of HLA was suggested from transcriptomics study, especially HLA-B and HLA-C alleles in infected Calu-3 cells ( 47 , 48 ). The expression difference of different alleles was confirmed, and changes in antigen presentation was also revealed in this study by MS.…”

Large scale transcriptional analysis of MHC class I haplotype diversity in sheep

“…While a larger data set is required to confirm these observations at the haplotype level in sheep; hierarchy in allelic expression associated with differences in peptide repertoires and disease progression has been reported in chicken and human MHC class I genes 40,44 . Indeed, evidence of haplotype dominance in expression of classical HLA class I genes has recently been reported following infection of cell lines with SARS‐Cov‐2 45 …”

Expression of MHC II in DRG neurons attenuates paclitaxel-induced cold hypersensitivity in male and female mice

“…However, by knocking out both copies of MHCII in TRPV1-lineage neurons, the percent of MHCII + neurons in the DRG of naïve female mice was severely reduced (70%), suggesting MHCII was indeed expressed in TRPV1-lineage neurons but only one parental allele was being expressed. Processes including X chromosome inactivation, random monoallelic expression, or allelic exclusion are known to cause this allelic imbalance or allele-specific expression (ASE) [ 49 ]. Epigenetic modifications (DNA methylation, histone modification, and microRNAs) contribute to ASE, and inflammatory mediators, specifically IFN-γ, are known to promote chromatin remodeling to enhance MHC expression [ 50 ].…”