Role of SARS-CoV-2-mediated Type I IFN antagonism in individuals with Down Syndrome

Project Summary Type I Interferons (IFN-Is) are cytokines with potent anti-viral and proinflammatory activities. As such theyare tightly regulated to provide enough antiviral effects while not causing over and health disrupting inflammation.Disorders where IFN-Is dysregulation is known to cause pathology are termed type I Interferonopathies. Down syndrome (DS) is the most common genetic cause of intellectual and developmental disabilities inchildren and young adults with Incidence in US of about 1 in 600 individuals. Individuals with DS often havecardiac and gastrointestinal abnormalities. Additionally, they have a number of immune-related problems fromincreased susceptibility to an array of infectious diseases to autoimmunity. Unfortunately, the exact molecularmechanism leading to these immune defects has not been elucidated. COVID-19 is a disease caused by a coronavirus, Severe Acute Respiratory Syndrome (SARS) -CoV-2.Infections by SARS-CoV-2 are now present in every country around the globe, causing unprecedented publichealth burden. SARS-CoV is known to interfere with IFN-I induction and signaling. To which extent SARS-CoV-2 can cause illness in individuals with DS is currently unknown. DS is, in most cases, caused by an extrachromosome 21, on which the receptors for type I Interferons (IFNAR1 and IFNAR2) are encoded. How thisgene dosage effects are contributing to SARS-CoV-2 pathophysiology is not understood. This proposal is builtaround the hypothesis that relative amounts of IFNAR1 and IFNAR2 are the essential factors controlling SARS-CoV-2 pathophysiology. To address this hypothesis, we propose to study DS patients in vitro at the molecularlevel to determine the functional significance of dose of these genes in regulating IFN pathway in humans duringSARS-CoV-2 infection. Deeper understanding of molecular regulation of IFN-I in DS in the context of SARS-CoV-2 will allow us tobetter understand how to approach clinical management of disease.