Genetic and Immuno-inflammatory Drivers of Post-acute Pulmonary Sequelae of SARS-CoV-2

The goal of this proposal will be to study the frequency, chronicity, and etiology of post-acute sequelae of SARS CoV-2 with protocols designed to characterize genetic and immuno-inflammatory factors that influence post-COVID complications. We will establish a cohort of 1200 or more deeply phenotyped SARS CoV-2 patients in order to determine the long-term effects of COVID-19 infection in distinct PASC cohorts. Patients will be categorized by the presence or absence of pulmonary symptoms. We will focus on changes in pulmonary lung function (DLCO and FVC, TLC) and 6-minute walk test (6MWT) at 3, 6, and 12 months and biannually thereafter for 5 years. To assess progressive pulmonary fibrosis, we will include x-rays and computerized tomography (CT) of the lung. To explore pathogenic mechanisms we will: 1) determine whether specific cytokine levels associate with the severity or progression of PASC-associated disease; and, 2) determine whether there is a characteristic autoantibody profile, including anti-cytokine antibodies, in PASC patients; 3) perform Global Diversity Array (GDA) chip analysis on 1200 patients to develop an unbiased genetic risk score for PASC; 4) determine whether specific genotypes: a) influence the severity or chronicity of PASC, including the development of Idiopathic Pulmonary Fibrosis or b) contribute to the sustained immunological responses in PASC patients. We will also characterize allele and haplotype variation in IL1RN, which encodes the interleukin-1 receptor antagonist (IL-1Ra), to evaluate how genetic variation modulates cytokine signaling, inflammatory resolution, and PASC disease trajectory. Genetic associations with PASC will be examined across groups defined by genome-wide genetic ancestry. Taken together, these novel studies are intended to better understand pathogenetic mechanisms of disease, which can lead to the identification of therapeutic targets and strategies for patients with post-acute sequelae.