Metabolic Dysfunction, Viral Persistence and Bioenergetic T-Cell Fatigue in Post-Acute SARS-CoV2

Introduction: Metabolic and immune dysfunction have been frequently reported among individuals with Long COVID. However, comprehensive studies with deep phenotyping for glucose metabolism, adipose tissue dysfunction, presence of virus in fat tissue and T cell bioenergetics and function have not been performed.

Objective: The objective of this study was to test the hypothesis that T-cell bioenergetic fatigue was associated with glucose intolerance, adipose tissue dysfunction and viral persistence of SARS-CoV-2 in subcutaneous adipocytes.

Methods: Aim 1: To determine the extent of adipose inflammation, glucose intolerance and cytokine release in post-acute sequelae of SARS-CoV-2 (PASC). Aim 2: To assess T-Cell Function and bioenergetics in relation to viral persistence and metabolic dysfunction. This was a case-control cohort study performed in 60 individuals enrolled in the longitudinal national RECOVER study of Long COVID. Forty Individuals with a high symptom score for Long COVID were matched for age, BMI and sex with twenty control subjects with few or no symptoms. We performed oral glucose tolerance tests, studies of insulin resistance, body composition by DEXA, serum adipocyte biomarkers, subcutaneous adipose tissue biopsies with RNAseq, fresh T Cell bioenergetics, in vitro T cell stimulation, and T cell surface antigen measurements.

Results: Forty Individuals with high symptom scores for Long COVID were matched for age, BMI and sex with twenty control subjects with few or no symptoms. Mean BMI (30.1) did not differ by group and there were no differences in fat mass although hip BMD was lower in the symptomatic group. Glucose tolerance and insulin resistance did not differ between groups, nor did T cell oxidative phosphorylation, although glycolytic pathways were increased in those affected with symptoms. SARS-CoV-2 virus was not detected in adipose tissue biopsies, nor were there any indicators of adipose tissue inflammation, although endotrophin levels were greater in those with symptoms vs those without. Indicators of chronic T cell activation including CD3/CD4, DPP-4 number and DPP-4 activity were higher in those with Long COVID symptoms, but no differences in serum cytokines or in vitro T cell cytokines were noted.

Conclusion/Discussion: In this case-control study we were unable to detect clinically apparent metabolic dysfunction, or viral persistence in adipose tissue among individuals suffering from Long COVID symptoms. We found no evidence of impaired T- cell bioenergetics in those with Long COVID. But we did detect significant enhancement in T cell glycolytic activity, and higher T cell surface markers (CD3/CD4) as well as higher plasma endotrophin levels for participants with a greater symptom burden, consistent with an ongoing immune stimulus in those affected individuals more than two years after SARS-CoV-2 infection.

Key Topics:

• Biomarker, in-depth phenotyping assays and in vitro studies using tissue and other biospecimens
• Clinical assessment and pathogenesis of clinical manifestations
• Viral persistence/reactivation