Although coronaviruses are typically believed to cause acute respiratory infections, emerging evidence suggests that viral antigen or perhaps even intact virus may be found outside of the respiratory system for extended periods of time following acute infection. Moreover, the data show that numerous non-respiratory tract tissues, including adipose tissue, can serve as a reservoir for the virus, suggesting that this infection may have long-term effects on multiple organ systems of the body. It is now recognized that a significant fraction of individuals diagnosed with COVID-19 will continue to exhibit a wide array of debilitating symptoms, collectively referred to as Post-Acute Sequalae of SARS-CoV-2 (PASC or Long-COVID), for weeks to months after infection. Given the enormous number of SARS-CoV-2 infected individuals who are likely to develop PASC, there is a critical need to better understand the risk factors associated with the different PASC manifestations and to develop appropriate interventions to treat these patients. To date, we know very little about the causes of PASC and do not have any understanding of whether pre-existing health issues (risk factors) can be used to predict whether someone will develop PASC or whether individuals with particular risk factors will develop PASC with a specific set of symptoms. The goal of this supplement is to determine whether metabolic changes associated with pre- existing obesity and Type II Diabetes (T2D) contribute to specific PASC-associated immune manifestations. In this supplement, we will test the hypothesis that metabolic risk factors can be used to identify patients with an inflammatory PASC syndrome that is characterized by persistent immune activation. To meet these goals, we have assembled >4000 consented participants (Enterprise cohort) who were previously hospitalized for COVID- 19 infection. We have access to their electronic medical records, can follow their symptoms longitudinally with on-line questionnaires and can obtain biologic samples from them. We have bio-banked blood samples, collected during the acute infection, from >1700 individuals, many of whom were diagnosed with PASC and have been followed longitudinally in our PASC clinic. Using these samples as well as additional blood samples that will be collected from PASC patients in the Enterprise cohort, we propose to: (i) determine whether obese and T2D PASC patients exhibit sustained anti-viral T and B cell responses; (ii) examine whether metabolic risk factors and inflammatory mediators linked to obesity and T2D correlate with the development of inflammatory PASC; and (iii) assess whether pre-existing obesity and associated metabolic disease predict the development of an inflammatory PASC syndrome. These studies are important as they will allow us to specifically interrogate the metabolic and immunologic factors that influence the pathophysiology of PASC in individuals with chronic co- morbidities that affect a large proportio...