Interferon hyperactivity, COVID19, and Down syndrome

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PROJECT SUMMARY. This is an application for an Urgent Competitive Revision to our Transformative R01 award funded by the NIH INCLUDE Project and NIAID titled ‘Understanding Down Syndrome as an Interferonopathy’. The central hypothesis of the parent award is that hyperactivation of interferon (IFN) signaling causes many of the developmental and clinical hallmarks of DS. In this revision, we will investigate the interplay between IFN hyperactivity, immune dysregulation, COVID19 pathology, and immunity against SARS-CoV-2. We hypothesize that IFN hyperactivity will modify the clinical course of COVID19 in DS, including long term immunological sequalae, while potentially impairing development of cellular and humoral immunity against SARS-CoV-2. Our Specific Aims are: 1. Determine the clinical and immunological characteristics of COVID19 in DS. It is increasingly evident that individuals with DS infected by SARS-CoV-2 are more likely to be hospitalized, develop secondary bacterial infections, and die at younger ages. However, many questions remain unanswered about the clinical course of COVID19 in DS. What are the risk factors for severe COVID19 in DS? Are there treatment modalities that are less or more effective in DS? What are the sequalae of SARS-CoV-2 infection in survivors with DS? Here, we will employ the National COVID Cohort Collaborative (N3C), the DS-Connect® registry, and the Human Trisome Project (HTP) cohort study to generate a definitive assessment of the clinical and immunological characteristics of COVID19 in DS. We will complete parallel analyses of the N3C database and data obtained by the HTP team via electronic health record abstraction and participant surveys to identify differences in early symptoms, immunological parameters, clinical course, risk factors, response to different treatment modalities, and long term sequalae, 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 investigation of the immune phenotype of people with DS has revealed strong dysregulation of T and B cell lineages, including changes that could impair the development of cellular and humoral immunity against SARS-CoV-2 and the response to SARS-CoV-2 vaccines. Now, supported by the DS-Connect® registry and the HTP cohort study, we will obtain biospecimens from individuals with DS that survived SARS-CoV-2 infection. We will include these samples in our ongoing pan-omics characterization of IFN hyperactivity and immune dysregulation in DS, while also investigating the development and duration of memory T and B cell responses and production of neutralizing antibodies specific for SARS-CoV-2. Altogether, these synergistic aims, which address multiple aspects of this NOSI, will advance our understanding of the impacts of trisomy 21 and IFN hyperactivity on COVID19 in DS, thus informing the rapid development of customized preventive, diagnostics, and therapeutic strategies for this at-risk population.