Metabolic and Epigenetic Mechanisms of PASC

Introduction: Our goal is to define pre-existing (i.e., due to co-morbidities) and post-infection metabolic and epigenetic signatures that mechanistically mediate the development, severity, and persistence of Long COVID symptoms. We will define how specific metabolites (i.e., Bile Acids) modulate cytokine production to regulate immune function and serve as long-term drivers of Long COVID through epigenetic changes which functionally alter cellular responses.

Objective: We will define specific metabolites and associated cytokines that mechanistically drive Long COVID through long-term epigenetic changes and identify therapeutic interventions that target these signatures to ameliorate Long COVID symptoms.

Methods: We will utilize a suite of complementary molecular, cellular and systems Immunology approaches to define metabolite and epigenetic mechanisms of Long COVID. Targeted metabolomics by mass spectrometry and multi-plexed ELISA will be used for direct quantification of metabolites and cytokines in longitudinal plasma samples before and during Long COVID. Flow cytometry will be performed to phenotype the identity and function of immune cells, and how these are regulated by metabolites signatures. scRNA-seq will be performed to identify the transcriptional signatures in distinct immune subsets regulated by metabolite mediators of post-acute sequelae of SARS-CoV-2 (PASC). Simultaneous scATAC-seq and scRNA-seq will be performed on select samples to define epigenetic alterations induced by metabolites which regulate the development of Long COVID and identify loci primed for altered expression versus those actively transcribed. AI modeling will define the critical metabolite and epigenetic features that mediate Long COVID and probe literature to validate findings and identify potential therapeutic interventions.

Results: In our current findings, we have identified distinct cytokine signatures associated with Long COVID comparing the co-morbidities of obesity (high IL-1, IL-6), HIV (high Type I and III IFNs), and lung disease (high IL-2, IFNg, IL-4, IL-17). AI modeling and LLM confirmed that IL-1 and IL-6 are the top cytokines associated with Long COVID and Obesity in our cohort and literature as well as identified these as two of the most potent cytokines reduced by GLP-1 treatment, providing a potential therapy for those with obesity and Long COVID.

Conclusion/Discussion: To date, we have identified distinct cytokine signatures of Long COVID resulting from different pre-existing co-morbidities which may mediate Long COVID through distinct, or convergent, mechanisms. We used our identified signatures of obesity and Long COVID to highlight a therapeutic intervention with GLP-1 to potentially reduce inflammation and symptoms in Long COVID.

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
• Collaborative and systems biology approaches
• Long COVID and other chronic conditions
• Long-term follow-up of the RECOVER Cohorts
• Validation of published studies on potential mechanisms of Long COVID using data and biospecimens from RECOVER cohorts