Airway epithelial hyperactivation of JAK-STAT signaling impairs type-III IFN responses during RSV infection in Down Syndrome [Bulk RNA-seq]

Trisomy 21 (TS21), commonly known as Down syndrome (DS), increases mortality risk due to respiratory syncytial virus (RSV) in children by nearly 9-fold. Interferon (IFN)-mediated JAK/STAT antiviral signaling is altered in DS given that four IFN receptor genes reside on chromosome 21. This study unveils an interferonopathy in TS21 pediatric airway epithelial cells (AECs), the primary point of entry and defense against RSV. Relative to euploid cells, TS21 AECs show reduced RSV infection levels accompanied by baseline hyperactivation of IFNJAK/STAT antiviral signaling. Conversely, in response to RSV infection, both the induction of IFN signaling and type-III IFN production are reduced in TS21 AECs compared to controls. JAK inhibition mitigates baseline IFN hyperactivation and increases type-III IFN antiviral response in TS21 AECs. Our findings identify hyperactivation of IFN-JAK/STAT in AECs of children with DS as a potentially targetable mechanism for reducing the lethal impact of RSV infection in this vulnerable population. Overall design: Three infant AECs were plated at 1.5 x 10^5 cells/well on collagen coated 6 well dishes (pureCol) for approximately 24 hours . After 24hr of plating, the cells were transitioned to serum free media. The cells were treated the next day with either IFN-?/IL-29 (100ng/mL) or IFN ß (1ng/mL) in serum free media.