ABSTRACT Down syndrome (DS), also known as trisomy 21, is the most common chromosomal abnormality among live- born infants. DS is associated with a disproportionate high risk for severe viral respiratory infections, a top cause of mortality in this vulnerable population. Nonetheless, the risk of DS patients to develop severe SARS- CoV-2 infections during the COVID-19 pandemic has been remarkably understudied. A major concern in DS individuals the risk to develop hyper-inflammatory responses manifested as cytokine storm and/or multisystem inflammatory syndrome in children. Indeed, people with DS exhibit hyper-activation of interferon (IFN) signaling because they have three copies of the chromosome 21, which encodes four of the six IFN receptors. Importantly, our team and others recently identified that IFNs are strong inducers of the angiotensin-converting enzyme 2 (ACE2), the cell entry receptor of SARS-CoV-2 in the human airway epithelium. The novel finding that SARS-CoV-2 may tap into the host IFN-driven airway epithelial antiviral response to enhance its infectivity represents a paradigm shift for the pathobiology of COVID19, particularly in individuals with DS. The overall goal of this application is to investigate, for the first time, the airway epithelial IFN-driven antiviral and pro- inflammatory responses in young children with DS. Our NIH-funded laboratory (R01HL141237) has the expertise to study the immunobiology of the airway epithelial cell (AEC) of young children, the age group with the highest risk for severe viral respiratory infections. Our central hypothesis is that the airway epithelium of DS children exhibits a dysregulated antiviral molecular program leading to enhanced production of pro-inflammatory cytokines and IFNs (Aim 1); and heightened responsiveness to IFNs leading to overexpression of ACE2 and increased susceptibility to SARS-CoV-2 infection (Aim 2). Defining the key innate cytokines/chemokines and the precise molecular pathways dysregulated in the AEC of DS individuals promises a unique opportunity to discover novel targets to treat severe viral respiratory infections, including SARS-CoV-2. This new knowledge may have long-lasting impact for people with DS by identifying potentially novel approaches to prevent severe respiratory infections caused by SARS-CoV-2 and other viruses (e.g. RSV) in children and adults with DS.

Public Health Relevance Statement: We will elucidate the antiviral, pro-inflammatory and IFN-induced responses in the nasal AECs of children with Down Syndrome (DS). This may provide the foundation to develop novel approaches to prevent severe respiratory infections caused by SARS-CoV-2 and other viruses (e.g. RSV) in children and adults with DS.