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

Trisomy 21 (TS21) or Down syndrome (DS) causes a ninefold increase in the mortality risk in children from otherwise non-lethal respiratory syncytial virus (RSV) infection. However, it is not known if this lethality is due to increased viral infectivity, or downstream antiviral response. We analyzed the pediatric airway epithelial cells (AECs) - the primary point of viral entry and defense and found that the antiviral IFN-JAK/STAT signaling response is hyperactivated in T21 cells relative to euploid cells. This is associated with decreased RSV infection in TS21 AECs. Conversely, upon exposure to RSV, both the induction of IFN signaling and type-III IFN production are diminished in TS21 AECs and in patients in vivo. Treating TS21 AECs with JAK inhibitor alleviated the baseline type-III IFN upregulation without impairing their ability to activate IFN response upon viral exposure. This identifies a potential approach to mitigate the impact of RSV on children with DS. Overall design: To investigate the cellular landscape of Trisomy21 samples in comparison to Euploid samples, we performed single cell RNAseq on cell cultures of nasal airway epithelium cells (AECs) An euplooid (BR61) and a trisomy 21 (TS21-6), Airway epithelium cell sample, was treated with sucrose solution (mock treatment) or RSV treated. A total of 8 samples were obtained, with 2 technical replicates each per genotype anc condition.