Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium

Abstract

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 CC-BY-NC-ND 4.0 International license was not certified by peer review) is the author/funder.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...

Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon

“…Existing data indicate that ACE2 is expressed primarily in the nasal and bronchial epithelium and is absent from immune cells (16). Given our prior data indicating that FP also exerts its inhibitory effects on immunity principally at the pulmonary epithelium (8,23), we next assessed whether suppressive effects on ACE2 were also observed following ex vivo ICS administration in cultured COPD bronchial epithelial cells (BECs, Fig 5a).…”

Viruses and asthma: the role of common respiratory viruses in asthma and its potential meaning for SARS‐CoV‐2

“…Studies found that the expression of TMPRSS2 in the airway epithelium was greatly upregulated by Th2 cytokines, especially by IL‐13; however, the same Th2 cytokines decreased the levels of ACE2 in nasal and bronchial epithelium. Respiratory allergy was also linked to a significant decrease in the expression of ACE2 20−23 . Interestingly, in a large cohort of asthmatic patients in the USA, it was found that the expression of ACE2 and TMPRSS2 was specifically increased in sputum cells of males, African Americans individuals, and patients suffering from diabetes mellitus 51 .…”

“…Moreover, an asthmatic background seems to modulate these two proteins differently depending on the group of patients in question (male versus female or African Americans versus Caucasians). However, and attending to the so‐far reported cases of asthma among patients with COVID‐19, the globally available data seem to indicate that Th2 inflammation linked to atopic asthma may not have a strong implication in a severe course of the disease 20−23 …”

“…In the pandemic of COVID‐19 induced by the novel coronavirus SARS‐CoV‐2, efforts have been made to find potential risk factors. Although the first scientific evidence seems to indicate that allergic asthma is not a strong risk factor for an increased severe infection of SARS‐CoV‐2, several studies have started to explore at a molecular and cellular level the relation between COVID‐19 and asthma 20−23 . Yet, little is known regarding the potential consequences and sequelae that SARS‐CoV‐2 infection can produce as such infection is characterized by a strong hyperinflammation and tissue remodelling.…”

The Intestinal Perspective of COVID-19: NOS2 and AOC1 Genes as Epidemiological Factors, and a Homeopathic Approach to their Functional Improvement

“…167 This supposes a negative correlation between both, where the upregulation of ACE2 means the downregulation of ACE. On the other hand, TMPRSS2 seems to be enhanced by interleukin-13 (IL-13), 168 which is a cytokine produced by lymphocytes Th2 cells, lymphocytes B (B-cells), mast cells, eosinophils, basophils, and alveolar macrophages (M2 cells) 169 ; so, there should be an increase in the activity of these immune cells during the infection. In addition, a recent study referring to the relationship between TMPRSS2 and IL-13 demonstrates the implication of the IFN family in the improvement of ACE2 for the virus to enter into nasal goblet secretory cells, lung type II pneumocytes, and ileal absorptive enterocytes.…”