The leading cause of hospitalization and death in children with trisomy 21 (TS21), also known as Down
syndrome (DS), is lower respiratory tract infection (LRTI). Children with DS have nine times higher risk of
hospitalization and mortality due to LRTIs caused by respiratory syncytial virus (RSV). Understanding the
mechanisms driving the high susceptibility to severe viral LRTI in DS is needed to develop novel therapeutic
strategies to treat this condition. As chromosome 21(HSA21) encodes four of the six known Interferon (IFN)
receptors, TS21 results in triplication of these receptor genes leading to IFN hyperactivation in DS. With the
central role of IFNs on antiviral defense, it remains puzzling how IFN hyperactivation contributes to severe viral
LRTIs in DS. Through preliminary studies we show that, compared to euploid controls, airway epithelial cells
(AECs) from children with DS exhibit IFN-induced dysregulation of NRF2, a transcription factor essential for the
antioxidant response required to limit RSV replication. The AECs of children with DS also show dysregulated
expression of BACH1 and its inhibitor miR-155, both of which are located on HSA21, and regulate NRF2-
dependent AEC antioxidant responses during viral infection. Thus, our results identify a novel mechanism of
impaired airway antiviral responses in TS21, and provide an unexpected molecular nexus between two widely
recognized cellular pathologies in DS - dysregulated IFN activation (interferonopathy) and oxidative imbalance.
Our central hypothesis is that hyperactivation of IFN in the airway epithelium of children with DS
dysregulates BACH1 signaling, leading to reduced antiviral and NRF2-driven antioxidant responses
and greater severity of viral respiratory infection. Our study will address the historical exclusion of DS
children from research related to airway antiviral immunity, and thus will have a transformative potential to
improve their health and survival. To elucidate the mechanisms of pathogenesis of severe viral respiratory
infections in DS and develop innovative precision medicine approaches for this vulnerable population, we
propose three aims: AIM 1: Define the role of IFN-induced BACH1 dysregulation during viral respiratory
infection in the airway epithelium of children with DS. AIM 2: Investigate how interferonopathy and altered
miR-155 expression dysregulates antioxidative and antiviral responses in the airway epithelium of children with
DS. AIM 3: Establish the association of dysregulated antioxidative and antiviral responses in DS with greater
disease severity during respiratory viral infection. The result of this human-based transformative study will
define a previously unrecognized targetable mechanism causing dysregulated anti-oxidative and antiviral
responses in TS21. This ground-breaking knowledge will greatly move forward our understanding of the
pathobiology of severe viral LRTI in DS and will provide the essential molecular foundation for the development
of new diagnostic tools and highly innovative therapies.