Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium

Abstract

Background The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. Methods We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. Results We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. Conclusions These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation

“…While awaiting data release via dbGaP, investigators may contact the senior author (Wenzel) of this study or go to the SARP website ( 46 ) to access to the data via the ancillary study mechanism for SARP. Count data for the SARP cohort was obtained from Stephanie Christianson (UCSF) and as published recently ( 47 ).…”

Identification of Novel Gene Signatures using Next-Generation Sequencing Data from COVID-19 Infection Models: Focus on Neuro-COVID and Potential Therapeutics

“…An increase in the expression of ACE2, a tissue-protective mediator during lung damage, was found to be associated with interferon signaling in airway epithelial cells, and SARS-CoV-2 could exploit interferon-mediated stimulation of ACE2 to augment infection ( Ziegler et al, 2020 ). The differential expression of genes that are necessary for SARS-CoV-2 interaction and subsequent host response determine susceptibility to COVID-19, disease progression, and recovery ( Kasela et al, 2021 ).…”

“…Single-cell RNA sequencing of COVID-19 infected bronchial epithelial cells and bronchioalveolar immune cells revealed important cellular and molecular processes implicated in COVID-19 infection at the single-cell level and provided information about the mechanisms of disease severity ( Liu T. et al, 2020 ; Liao et al, 2020 ; Zhou et al, 2020 ). Notably, IL-17-associated signaling was significantly increased but not Th2-related inflammation following COVID-19 infection ( Kasela et al, 2021 ) . A recent study showed that SARS-CoV-2 infection caused a twofold higher induction of interferon stimulation compared to SARS-CoV in Calu-3 human epithelial cells and subsequent induction of cytokines such as IL6 or IL-10 ( Wyler et al, 2021 ).…”

The Drosophila melanogaster ACE2 ortholog genes are differently expressed in obesity/diabetes and aging models: Implications for COVID-19 pathology

“…Thus, the influence of diet on ACE2 mRNA expression is based on interventions by dietary restrictions or weight loss [53] , [54] . Also, research related to ACE2 mRNA expression in organs, such as the heart or liver, is obtained from biopsies [55] , [56] . These facts reinforce the importance of an animal model for in vivo and ex vivo COVID-19 studies.…”