Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.
32Coronavirus disease 2019 outcomes vary from asymptomatic infection to 33 death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, 34 ACE2, and the spike protein activator, TMPRSS2. Here we explore the role of genetics 35 and co-expression networks in regulating these genes in the airway, through the 36 analysis of nasal airway transcriptome data from 695 children. We identify expression 37 quantitative trait loci (eQTL) for both ACE2 and TMPRSS2, that vary in frequency 38 across world populations. Importantly, we find TMPRSS2 is part of a mucus secretory 39 network, highly upregulated by T2 inflammation through the action of interleukin-13, and 40 that interferon response to respiratory viruses highly upregulates ACE2 expression. 41Finally, we define airway responses to coronavirus infections in children, finding that 42 these infections upregulate IL6 while also stimulating a more pronounced cytotoxic 43 immune response relative to other respiratory viruses. Our results reveal mechanisms 44 likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes. 45 46 47 48 IL-13), which is common in both children and adults and has been associated with the 87 development of both asthma and COPD in a subgroup of patients [11][12][13] . T2 cytokines are 88 known to greatly modify gene expression in the airway epithelium, both through 89 transcriptional changes within cells and epithelial remodeling in the form of mucus 90 metaplasia 11, 14, 15 . Microbial infection is another strong regulator of airway epithelial 91 expression. In particular, respiratory viruses can modulate the expression of thousands 92 of genes within epithelial cells, while also recruiting and activating an assortment of 93 immune cells [16][17][18] . Even asymptomatic nasal carriage of respiratory viruses, which is 94 especially common in childhood, has been shown to be associated with both genome-95 wide transcriptional re-programming and infiltration of macrophages and neutrophils in 96 the airway epithelium 19 , demonstrating how viral infection can drive pathology even 97 without overt signs of illness. 98 99 . CC-BY-NC-ND 4.0 International license was not certified by peer review) is the author/funder. It is made available under a Genetic variation is another factor that may regulate gene expression in the airway 100 epithelium. Indeed, expression quantitative trait loci (eQTL) analyses carried out in 101 many tissues have suggested that as many as 70% of genes expressed by a tissue or 102organ are under genetic control 20 . Severity of human rhinovirus (HRV) respiratory illness 103 has specifically been associated with genetic variation in the epithelial genes CDHR3 21 104 and the ORMDL3 22 and, given differences in genetic variation across world populations, 105 it is possible that functional genetic variants in SARS-CoV-2-related genes could partly 106 explain population differences in COVID-19 clinical outcomes. 107 108 Finally, there are important questions regarding the host response to SARS-CoV-2...
NF-κB activation within the epithelium has been implicated in the pathogenesis of asthma, yet the exact role of epithelial NF-κB in allergen-induced inflammation and airway remodeling remains unclear. In the present study, we utilized an intranasal House Dust Mite (HDM) extract exposure regimen time course in BALB/c mice to evaluate inflammation, NF-κB activation, airway hyperresponsiveness (AHR), and airway remodeling. We utilized CC10-IκBαSR transgenic mice to evaluate the functional importance of epithelial NF-κB in response to HDM. After a single exposure of HDM, mRNA expression of pro-inflammatory mediators was significantly elevated in lung tissue of WT mice, in association with increases in nuclear RelA and RelB, components of the classical and alternative NF-κB pathway, respectively, in the bronchiolar epithelium. In contrast, CC10-IκBαSR mice displayed marked decreases in nuclear RelA and RelB and mRNA expression of pro-inflammatory mediators compared to WT mice. After 15 challenges with HDM, WT mice exhibited increases in inflammation, airway hyperresponsiveness, mucus metaplasia and peri-bronchiolar fibrosis. CC10-IκBαSR transgenic mice displayed marked decreases in neutrophilic infiltration, tissue damping, and elastance parameters, in association will less peri-bronchiolar fibrosis and decreases in nuclear RelB in lung tissue. However, central airway resistance and mucus metaplasia remained elevated in CC10-IκBαSR transgenic mice, in association with continued presence of lymphocytes, and partial decreases in eosinophils and IL-13. The current study demonstrates that following airway exposure with an asthma-relevant allergen, activation of classical and alternative NF-κB pathways occur within the airway epithelium and may coordinately contribute to allergic inflammation, AHR and fibrotic airway remodeling.
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