PROJECT SUMMARY SARS-CoV-2 infections in children are mostly milder and less lethal than in adults. This lower incidence of relevant disease associated with SARS-CoV-2 has surprisingly also been observed for children with asthma, the most common chronic respiratory and inflammatory disease in children. As social distancing and masks have dramatically but temporarily decreased the spread of common viral respiratory infections, this created the positive effect of a significant decrease of viral-triggered asthma in children. The growing prevalence of SARS-CoV-2 infection in children and the resurgence of non-SARS-CoV-2 respiratory viral infections make it critical and timely to understand how SARS-CoV-2 infection shapes respiratory outcomes and immune responses to other respiratory viruses and the upcoming SARS-CoV-2 vaccines. In addition to a strong genetic predisposition, asthma is strongly linked to viral respiratory infections, and infectious stimuli can have long-term epigenetic consequences that shape immune responses to subsequent infections. We propose that a common genetic variation that alters sphingolipid levels in children with asthma may also result in limited pathogenesis of SARS-CoV-2 in children with asthma. This proposal aims to test the hypothesis is that common genetic variation in asthma moderate age-dependent outcomes and immune responses to SARS-CoV-2 infection and vaccines utilizing an NYC pediatric asthma cohort that was started early in the pandemic. This cohort is uniquely suited to the hypothesis as it (1) includes children of all ages with and without asthma; (2) is enriched for children from ethnic, racial, and socioeconomic backgrounds associated with health disparities and high exposure to SARS- CoV-2; and (3) has already enrolled more than three hundred with a high antibody positivity rate since May 2020. The availability of detailed questionnaire data on asthma and SARS-CoV-2 exposure, biospecimen that include blood (including stored PBMC), and nasal samples will enable us to address these three Specific Aims, to (1) determine the age-dependent effect of SARS-CoV-2 infection on subsequent respiratory health in asthmatic children; (2) define the epigenetic and transcriptomic effect of SARS-CoV-2 infection on hematopoietic stem cells, and (3) define the effects of common genetic asthma risk alleles on responses to SARS-CoV-2 infection of nasal epithelial cells and subsequent infection with respiratory syncytial virus and rhinovirus. These studies will be supported by a team with expertise in viral immunology, pediatric asthma, and epigenetics of immune responses and will inform on age- and disease- specific impact and mechanisms of SARS-CoV-2 and common respiratory viruses in children.