Tissue and Organ Specific Human B Cell Immunity: Supplement — Metabolic Risk Factors and Inflammation in PASC Development

Introduction: Patients experiencing severe disease following SARS-CoV-2 infection often have underlying chronic health conditions including obesity and type 2 diabetes. These metabolic diseases cause inflammation, which contributes to the development of Long COVID (LC). We used our Deep South Enterprise COVID cohort, which is heavily biased toward obese patients, to identify obese individuals who either did or did not develop LC.

Objective: We leveraged our unique obese LC cohort to identify the underlying metabolic and persistent immune inflammatory changes that are associated with LC.

Methods: In this project, we (i) determined whether obese LC patients exhibited sustained anti-viral T and B cell responses, (ii) examined whether metabolic risk factors and inflammatory mediators linked to obesity correlated with persistent anti-viral responses in LC patients and (iii) assessed whether pre-existing obesity and associated metabolic disease predicted development of LC. We performed phone and in person surveys to identify obese individuals from the UAB Enterprise cohort who developed LC (LC+) or did not develop LC (LCneg). We measured inflammatory mediators and metabolites in serum and plasma and performed flow cytometry and single cell RNA-sequencing analysis on cells isolated from blood (PBMCs) and fat biopsies collected from obese LC+ and LCneg individuals. We used electronic health data to test whether changes in cardiometabolic disease syndrome (CMDS) scores predicted which individuals would develop LC.

Results: Patients whose CMDS score (based on body mass index, systolic and diastolic blood pressure, HDL, LDL, triglycerides and glucose levels) increased by 10 points post-SARS-CoV-2 infection had an 1.84-fold increased risk of developing LC (p<0.0001). We identified a subset of inflammatory mediators and metabolites (10-12 analytes) that were significantly increased (p<0.0001) in LC+ individuals and observed a highly significant difference in the activation status of immune cells residing in the fat of LC+ obese individuals. Analysis is still ongoing, and our preliminary findings may change pending final analysis.

Conclusion/Discussion: Obese individuals exhibit chronic inflammation and increased cardiometabolic disease syndrome. Those individuals whose CMDS score continues to increase post-acute infection are at greater risk for development of LC. Obese LC+ individuals exhibit an extreme inflammatory signature and immune dysfunction compared to than obese LCneg individuals and that inflammatory signature is best observed in the fat rather than in blood.

Key Topics:

• Assay and in vitro studies to gain mechanistic insights
• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Chronic immune dysfunction
• Clinical assessment and pathogenesis of clinical manifestations
• Clinical manifestations of chronic viral infections, biological pathways, immune-autoimmune disorders, systems, organs, or diseases
• Collaborative and systems biology approaches,Intersectionality of social determinants of health, built environments and/or pre-existing conditions and the risk for development or severity of Long COVID
• Remaining gaps in tissue-specific manifestations of Long COVID
• Viral persistence/reactivation