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

Environments and Asthma in Latino Americans II study (GALA II). This analysis 171 identified 54 co-expression networks representing cell type-specific expression 172 programs such as ciliogenesis, mucus secretion, and pathways of immunity and airway 173 inflammation (Supplementary Table 2 ). The TMPRSS2 gene was contained within one 174 of a set of three highly correlated networks exhibiting strong enrichments for mucus 175 Supplementary Table 4 ). In contrast, we found ACE2 expression to be strongly 192 negatively correlated with expression of both T2 networks (pink: r=-0.61, p=3e-72, 193 saddle brown: r=-0.7, p=2e-102, Figure 2e ,f). To identify subjects with high and low T2 194 inflammation, we hierarchically clustered all subjects based on the expression of genes 195 in the canonical T2 network (saddle brown). This resulted in the identification of two 196 distinct groups we labeled as T2-high (n=364) and T2-low (n=331) (Supplementary 197 Figure 1a ). We found that this expression-derived T2 status was strongly associated 198 with traits known to be driven by T2 inflammation including IgE levels, exhaled nitric Table 2) . Clustering of subjects based on the interferon 240 response network genes resulted in two groups, one highly (interferon-high=78) and 241 one lowly (interferon-low=617) expressing these interferon response network genes 242 (Supplementary Figure 2) . We found that ACE2 expression was 1.7-fold higher in the 243 interferon-high vs. interferon-low group (Figure 4d ). In a previous study, we found that 244 children with nasal gene expression characteristic of the interferon network tended to be 245 infected with a respiratory virus, despite being asymptomatic 19 . To explore the 246 possibility of this relationship in our current dataset, we metagenomically analyzed the 247 RNA-seq data for all subjects to identify those harboring reads for a respiratory virus. 248