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

Satria P. Sajuthi; Peter DeFord; Nathan D. Jackson; Michael T. Montgomery; Jamie L. Everman; Cydney L. Rios; Elmar Pruesse; James D. Nolin; Elizabeth G. Plender; Michael E. Wechsler; Angel CY Mak; Celeste Eng; Sandra Salazar; Vivian Medina; Eric M. Wohlford; Scott Huntsman; Deborah A. Nickerson; Soren Germer; Michael C. Zody; Gonçalo Abecasis; Hyun Min Kang; Kenneth M. Rice; Rajesh Kumar; Sam Oh; Jose Rodriguez-Santana; Esteban G. Burchard; Max A. Seibold

were instead most strongly enriched among neutrophils, as well as eosinophils, 382 macrophages, and monocytes. Furthermore, through pathway analysis we identified 383 multiple pathways related to cytotoxic T cell and NK cell activity that were enriched 384 either specifically or more dramatically among CoV DEGs compared to HRV DEGs 385 In the current study, we reasoned that population variation in upper airway expression 394 of the ACE2 receptor for SARS-CoV-2 and the virus-activating TMPRSS2 protease, 395 would drive infection susceptibility and disease severity. We therefore deployed network 396 and eQTL analysis of nasal airway epithelial transcriptome data from a large cohort of 397 healthy and asthmatic children to determine mechanisms associated with airway 398 expression of these genes, and their relative power in explaining variation in the 399 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.09.034454 doi: bioRxiv preprint expression of these genes among children. We observed only weak associations with 400 asthma status, age, and gender among children aged 8-21 years. Moreover, although 401 we found that genetics does influence expression of these genes, the effect of this 402 variation was small in comparison to the dramatic influence of T2 cytokine-driven 403 inflammation on both ACE2 (downregulation) and TMPRSS2 (upregulation) expression 404 levels. We found an equally important role for viral-driven interferon inflammation in 405 regulating levels of ACE2 in the airway. Additionally, through study of in vivo upper 406 airway CoV subfamily infections, we not only identify inflammatory regulators of these 407