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

Abstract

Coronavirus disease 2019 (COVID-19) outcomes vary from asymptomatic infection to death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, ACE2, and the spike protein activator, TMPRSS2. 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 (eQTL) for both <i>ACE2</i> and <i>TMPRSS2</i>, that vary in frequency across world populations. Importantly, we find <i>TMPRSS2</i> is part of a mucus secretory network, highly upregulated by T2 inflammation through the action of interleukin-13, and that interferon response to respiratory viruses highly upregulates <i>ACE2</i> expression. Finally, we define airway responses to coronavirus infections in children, finding that these infections upregulate <i>IL6</i> while also stimulating a more pronounced cytotoxic immune response relative to other respiratory viruses. Our results reveal mechanisms likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.