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

While the ACE2 eQTL variant, rs181603331, was associated with a notable decrease in 314 ACE2 levels, it only accounted for 1.2% of the variance, reflecting the low frequency of 315 this variant in our population. Increasing age and asthma diagnosis were both 316 associated with small decreases in ACE2 expression, although both variables 317 accounted for less than 2% of the variance, and sex was not a significant predictor 318 (Table 1) . 319 320 Similar modeling of TMPRSS2 expression found that T2-high status dramatically 321 increased expression, with an effect size 5.4x larger than any other variable, capturing 322 33% of total variation in TMPRSS2 (Table 1) Table 5 ). This allowed us to explore airway 334 transcriptomic responses to infection with coronavirus subfamily viruses specifically, 335 which will likely most resemble responses to SARS-CoV-2. To increase the likelihood 336 that these subjects were experiencing an active viral infection, we limited our analysis to 337 the 11 most highly infected subjects, comparing them to all subjects not infected with a 338 virus (n=571). To allow us to discriminate CoV-enhanced responses from those that are 339 more general to respiratory viruses, we also established a virus control group composed 340 of the 37 subjects highly infected with human rhinovirus species (HRV) (Supplementary 341 Table 6 ). We first compared expression of genes in the cytotoxic immune response 342 (purple) network and interferon response (tan) network (discussed earlier; see Figure 343 4a, b) among these virus infected groups, and found that both networks were more 344 highly expressed in virus-infected individuals (Figure 6a, b) . Moreover, while the 345 induction in interferon response was similar for both CoV and HRV groups, induction in 346 the cytotoxic immune response was considerably higher in CoV-infected (ΔE g = 0.049) 347 compared to HRV-infected individuals (ΔE g = 0.032, Figure 6b ). 348