Down Syndrome Alters Type-III IFN and Pro-Inflammatory Airway Epithelial Responses to RSV Infection

Trisomy 21 (TS21), also known as Down syndrome (DS), increases pediatric mortality risk due to respiratory syncytial virus (RSV) by ninefold. However, the underlying immunological basis remains unclear. To define the biological implications of TS21 in airway epithelial cells (AECs), the primary site of respiratory virus entry and host defense, in this study we investigated RSV-induced responses in primary nasal AECs from euploid and trisomic pediatric donors. We employed comprehensive approaches to assess baseline interferon (IFN)-JAK/STAT signaling, viral infectivity, and the production of type III IFN /λ1, pro-inflammatory cytokines, and chemokines, before and after RSV exposure.TS21 AECs exhibited baseline hyperactive IFN-JAK/STAT signaling and reduced RSV infectivity but also showed impaired type-III IFN responses during viral infection. Furthermore, TS21 AECs demonstrated a robust pro-inflammatory state, with upregulated leukocyte/neutrophil chemotaxis pathways and heightened CXCL5/CXCL10 production before and after RSV exposure. This pattern was recapitulated in infants with DS who had severe viral bronchiolitis, exhibiting a dysregulated airway immune response characterized by diminished type-III IFN and excessive CXCL5/CXCL10 production. Our results suggest that RSV severity in DS is not due to enhanced viral infectivity but rather to dysregulated airway pro-inflammatory responses, offering new therapeutic opportunities to mitigate the severity of RSV infection in children with DS.