Multi-omic analysis of long COVID patients reveals obesity-associated metabolic dysfunction and inflammation in adipose-residing immune cells 2334840

Abstract Introduction Long COVID is a chronic disease with potentially debilitating symptoms that affects millions of patients worldwide. Affected individuals often suffer from chronic inflammation and metabolic dysfunction, which may drive the chronic fatigue and brain fog characteristic of long COVID. Given the severity of symptoms and the high number of affected patients, understanding the causes and risk factors of this condition is crucial. Obesity is a known comorbidity for long COVID and drives immune and metabolic dysregulation. Thus, we hypothesized that obesity would exacerbate the underlying processes that contribute to long COVID. Methods To address this hypothesis, we performed multi-omic analyses on a cohort of patients with and without long COVID (LC+/-. These patients were then analyzed across BMI ranges (20-62). We performed serum proteomics and metabolomics. scRNAseq was also performed to determine the transcriptional profile of PBMCs and immune cells derived from subcutaneous adipose tissue in these patients. Results Our analysis revealed elevated levels of pro-inflammatory molecules in the serum of LC+ individuals. Furthermore, we observed enrichment of inflammatory gene signatures in a subset of PBMCs in LC+ patients and evidence of metabolic dysfunction. We next examined the adipose-residing immune cells where we observed widespread enrichment of inflammatory and anti-viral signatures in the LC+ individuals. Of note, the enrichment and breadth of these signatures correlated with patient BMI, as LC+ patients with higher BMIs appeared to have more widespread anti-viral signatures and metabolic dysfunction. Conclusion Taken together our data indicate that obesity exacerbates the immune and metabolic dysfunction that are hallmarks of long COVID. Given that patients with obesity have greater adiposity these data suggest that targeting adiposity may be an effective strategy in treatment of long COVID. Indeed, preliminary data suggests that GLP-1 agonists can provide relief for long COVID patients. Funding Source NIH RECOVER initiative Topic Categories Computational and Systems Immunology (COMP)