IFN responses and SARS-CoV-2 Receptor ACE2 Expression in the airway epithelium of young children with Down Syndrome

ABSTRACTDown 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 topcause 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 DSindividuals the risk to develop hyper-inflammatory responses manifested as cytokine storm and/or multisysteminflammatory syndrome in children. Indeed, people with DS exhibit hyper-activation of interferon (IFN) signalingbecause 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-convertingenzyme 2 (ACE2), the cell entry receptor of SARS-CoV-2 in the human airway epithelium. The novel findingthat SARS-CoV-2 may tap into the host IFN-driven airway epithelial antiviral response to enhance its infectivityrepresents a paradigm shift for the pathobiology of COVID19, particularly in individuals with DS. The overallgoal 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 theexpertise to study the immunobiology of the airway epithelial cell (AEC) of young children, the age group withthe highest risk for severe viral respiratory infections. Our central hypothesis is that the airway epitheliumof DS children exhibits a dysregulated antiviral molecular program leading to enhanced production ofpro-inflammatory cytokines and IFNs (Aim 1); and heightened responsiveness to IFNs leading tooverexpression of ACE2 and increased susceptibility to SARS-CoV-2 infection (Aim 2). Defining the keyinnate cytokines/chemokines and the precise molecular pathways dysregulated in the AEC of DS individualspromises a unique opportunity to discover novel targets to treat severe viral respiratory infections, includingSARS-CoV-2. This new knowledge may have long-lasting impact for people with DS by identifying potentiallynovel approaches to prevent severe respiratory infections caused by SARS-CoV-2 and other viruses (e.g.RSV) in children and adults with DS.