Allelic imbalance of HLA-B expression in human lung cells infected with coronavirus and other respiratory viruses

Zhang, Yuanxu; Sun, Yisheng; Zhu, Han-Ping; Hong, Hai; Jiang, Jianmin; Yao, Pingping; Liao, Huaxin; Zhang, Yan Feng

doi:10.1038/s41431-022-01070-5

Cited by 11 publications

(11 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…reported allelic imbalances across HLA-B alleles in lung cell lines infected by SARS-CoV-2 using an alternative methodological approach. The authors offered three non-exclusive biologically plausible mechanisms to explain the differential haplotype expression: (i) the activation/silencing of one allele is attributed to pathological effects, (ii) independent regulation of the transcription of both alleles, and (iii) the presence of cis-acting regulatory elements ( 27 ). In our study, the occurrence of DASE sites in the BRD2 gene mapping to the HLA chromosomal region corroborates the cis-acting regulatory elements’ hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Expression quantitative trait loci (eQTL) analysis ( 24 , 25 ) is often used to identify causal regulatory variants from GWAS, which also requires many samples besides being deeply influenced by interindividual differences ( 26 ). SARS-CoV-2 infection is known to promote imbalances in the expression of genetic variants across the human genome ( 27 ). But it still needs to be determined what their functional effects are because figuring out the links between genotype and phenotype in people with different genetic backgrounds requires analyzing many transcriptomes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2023

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

show abstract

“…It is advantageous to have enhanced binding capabilities of HLA molecules for viral peptides such as from SARS-CoV-2, on the cell surface of antigen-presenting cells. For example, Zhang et al ( 2022 ) showed an increased HLA-B18:01/B44:03 allelic fold change in SARS-CoV-2-infected A549 cells (Zhang et al 2022 ). New SARS-CoV-2 mutations may modify HLA expression, which may help explain immune response evasion.…”

Section: Hla Overviewmentioning

confidence: 99%

The immunogenetics of COVID-19

Hollenbach

Srivastava

2022

Immunogenetics

View full text Add to dashboard Cite

The worldwide coronavirus disease 2019 pandemic was sparked by the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) that first surfaced in December 2019 (COVID-19). The effects of COVID-19 differ substantially not just between patients individually but also between populations with different ancestries. In humans, the human leukocyte antigen (HLA) system coordinates immune regulation. Since HLA molecules are a major component of antigen-presenting pathway, they play an important role in determining susceptibility to infectious disease. It is likely that differential susceptibility to SARS-CoV-2 infection and/or disease course in COVID-19 in different individuals could be influenced by the variations in the HLA genes which are associated with various immune responses to SARS-CoV-2. A growing number of studies have identified a connection between HLA variation and diverse COVID-19 outcomes. Here, we review research investigating the impact of HLA on individual responses to SARS-CoV-2 infection and/or progression, also discussing the significance of MHC-related immunological patterns and its use in vaccine design.

show abstract

“…Zhang et al reported allelic imbalances across HLA-B alleles in lung cell lines infected by SARS-CoV-2 using an alternative methodological approach. The authors offered three non-exclusive biologically plausible mechanisms to explain the differential haplotype expression: (i) the activation/silencing of one allele is attributed to pathological effects, (ii) independent regulation of the transcription of both alleles, and (iii) the presence of cis-acting regulatory elements (27). In our study, the occurrence of DASE sites in the BRD2 gene mapping to the HLA chromosomal region corroborates the cis-acting regulatory elements’ hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Expression quantitative trait loci (eQTL) analysis (24,25) is often used to identify causal regulatory variants from GWAS, which also requires many samples, despite being deeply influenced by interindividual differences (26). SARS-CoV-2 infection is known to promote imbalances in the expression of genetic variants across the human genome (27). But it is still not clear what their functional effects are because figuring out the links between genotype and phenotype in people with different genetic backgrounds requires analyzing a large number of transcriptomes.…”

Section: Introductionmentioning

confidence: 99%

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

Francisco

Temerozo

Ferreira

et al. 2022

Preprint

View full text Add to dashboard Cite

Cell 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 disease. We aim to estimate the transcriptome-wide impact of SARS-CoV-2 infection by analyzing eSNVs. We 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. We 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. Independent 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.

show abstract

Allelic imbalance of HLA-B expression in human lung cells infected with coronavirus and other respiratory viruses

Cited by 11 publications

References 50 publications

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

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

The immunogenetics of COVID-19

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

Contact Info

Product

Resources

About