Interferon hyperactivity, COVID19, and Down syndrome

PROJECT SUMMARY.This is an application for an Urgent Competitive Revision to our Transformative R01 award funded by the NIHINCLUDE Project and NIAID titled 'Understanding Down Syndrome as an Interferonopathy'. The centralhypothesis of the parent award is that hyperactivation of interferon (IFN) signaling causes many of thedevelopmental and clinical hallmarks of DS. In this revision, we will investigate the interplay between IFNhyperactivity, immune dysregulation, COVID19 pathology, and immunity against SARS-CoV-2. We hypothesizethat IFN hyperactivity will modify the clinical course of COVID19 in DS, including long term immunologicalsequalae, while potentially impairing development of cellular and humoral immunity against SARS-CoV-2. OurSpecific Aims are:1. Determine the clinical and immunological characteristics of COVID19 in DS. It is increasingly evidentthat individuals with DS infected by SARS-CoV-2 are more likely to be hospitalized, develop secondary bacterialinfections, and die at younger ages. However, many questions remain unanswered about the clinical course ofCOVID19 in DS. What are the risk factors for severe COVID19 in DS? Are there treatment modalities that areless or more effective in DS? What are the sequalae of SARS-CoV-2 infection in survivors with DS? Here, wewill employ the National COVID Cohort Collaborative (N3C), the DS-Connect® registry, and the Human TrisomeProject (HTP) cohort study to generate a definitive assessment of the clinical and immunological characteristicsof COVID19 in DS. We will complete parallel analyses of the N3C database and data obtained by the HTP teamvia electronic health record Abstract: Ion and participant surveys to identify differences in early symptoms,immunological parameters, clinical course, risk factors, response to different treatment modalities, and long termsequalae, with emphasis on potential differences by age, sex, race/ethnicity, and geography.2. Investigate the immune phenotype of a cohort of COVID19 survivors with DS. Our extensive investigationof the immune phenotype of people with DS has revealed strong dysregulation of T and B cell lineages, includingchanges that could impair the development of cellular and humoral immunity against SARS-CoV-2 and theresponse to SARS-CoV-2 vaccines. Now, supported by the DS-Connect® registry and the HTP cohort study, wewill obtain biospecimens from individuals with DS that survived SARS-CoV-2 infection. We will include thesesamples in our ongoing pan-omics characterization of IFN hyperactivity and immune dysregulation in DS, whilealso investigating the development and duration of memory T and B cell responses and production of neutralizingantibodies specific for SARS-CoV-2.Altogether, these synergistic aims, which address multiple aspects of this NOSI, will advance our understandingof the impacts of trisomy 21 and IFN hyperactivity on COVID19 in DS, thus informing the rapid development ofcustomized preventive, diagnostics, and therapeutic strategies for this at-risk population.