%0 Journal Article %J Nat Commun %D 2020 %T Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium. %A Sajuthi, Satria P %A DeFord, Peter %A Li, Yingchun %A Jackson, Nathan D %A Montgomery, Michael T %A Everman, Jamie L %A Rios, Cydney L %A Pruesse, Elmar %A Nolin, James D %A Plender, Elizabeth G %A Wechsler, Michael E %A Mak, Angel C Y %A Eng, Celeste %A Salazar, Sandra %A Medina, Vivian %A Wohlford, Eric M %A Huntsman, Scott %A Nickerson, Deborah A %A Germer, Soren %A Zody, Michael C %A Abecasis, Gonçalo %A Kang, Hyun Min %A Rice, Kenneth M %A Kumar, Rajesh %A Oh, Sam %A Rodriguez-Santana, Jose %A Burchard, Esteban G %A Seibold, Max A %K Angiotensin-Converting Enzyme 2 %K Betacoronavirus %K Child %K Coronavirus Infections %K COVID-19 %K Epithelial Cells %K Gene Expression Profiling %K Gene Expression Regulation %K Genetic Variation %K Host-Pathogen Interactions %K Humans %K Inflammation %K Interferons %K Interleukin-13 %K Middle Aged %K Nasal Mucosa %K Pandemics %K Peptidyl-Dipeptidase A %K Pneumonia, Viral %K SARS-CoV-2 %K Serine Endopeptidases %K Virus Internalization %X

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.

%B Nat Commun %V 11 %P 5139 %8 2020 10 12 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33046696?dopt=Abstract %R 10.1038/s41467-020-18781-2 %0 Journal Article %J bioRxiv %D 2020 %T Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium. %A Sajuthi, Satria P %A DeFord, Peter %A Jackson, Nathan D %A Montgomery, Michael T %A Everman, Jamie L %A Rios, Cydney L %A Pruesse, Elmar %A Nolin, James D %A Plender, Elizabeth G %A Wechsler, Michael E %A Mak, Angel Cy %A Eng, Celeste %A Salazar, Sandra %A Medina, Vivian %A Wohlford, Eric M %A Huntsman, Scott %A Nickerson, Deborah A %A Germer, Soren %A Zody, Michael C %A Abecasis, Gonçalo %A Kang, Hyun Min %A Rice, Kenneth M %A Kumar, Rajesh %A Oh, Sam %A Rodriguez-Santana, Jose %A Burchard, Esteban G %A Seibold, Max A %X

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 and , that vary in frequency across world populations. Importantly, we find 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 expression. Finally, we define airway responses to coronavirus infections in children, finding that these infections upregulate 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.

%B bioRxiv %8 2020 Apr 10 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/32511326?dopt=Abstract %R 10.1101/2020.04.09.034454