Metabolic, viral, and immune phenotypes in long COVID, 2026, Emery et al.

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Metabolic, viral, and immune phenotypes in long COVID

Spoiler: Authors

Emery, Ivette F; Sahagun, Seynt Jiro; Zunica, Elizabeth R M; Axelrod, Christopher; Beyl, Robbie A; Cho, Eunhan; Spielmann, Guillaume; Costa, Samantha; DeKay, Joanne T; Chlebek, Carolyn; Amano, Shinya; Stevens, Katherine; Scherer, Philipp E; Bu, Dawei; Javidan, Aida; Finlin, Brian S; Zhang, Xiaohua D; Nikolajczyk, Barbara; Blish C, Catherine; Bramante, Carolyn; McLaughlin, Tracey; DeLine-Caballero, Soneida; Ratnasiri, Kalani; Mangalanathan, Uma; Li, Jonathan Z; Leeman, Brooke M; Edelstein, Gregory; Karlson, Elizabeth W; Kirwan, John P; Kern, Philip A; Ryzhov, Sergei; Rosen, Clifford J

CONTEXT
Long COVID is characterized by persistent symptoms ≥ 3 months after acute SARS-CoV-2 infection. To date, the underlying pathophysiology is unclear.

OBJECTIVE
To characterize the immune and metabolic features of Long COVID and the potential role of viral persistence in adipose tissue.

DESIGN
Case-control, cross-sectional study under the RECOVER initiative.

SETTING
Maine, Louisiana, and Kentucky.

PARTICIPANTS
Adults from the RECOVER study with high or low symptom burden assessed by the PROMIS scoring system or the Long COVID RECOVER Index (LCRI), matched by age, sex, BMI comparing post infected individuals with Long COVID vs those without sequelae.

MAIN OUTCOME MEASURES
The primary outcome was a difference in T cell mitochondrial respiration by symptom severity. Secondary outcomes included glucose tolerance, body composition, T cell surface markers, subcutaneous adipose biopsy.

RESULTS
There were 54 participants, 80% female, mean age was 51.7 years, mean BMI 31. Time from initial infection was 894 days. The participant cohort by symptom burden was elucidated using a PROMIS symptom score subdivided by the following: High Symptom Burden (HSB) >15:n=25, Intermediate Symptom Burden (ISB) 10-15: n=14 and Low Symptom Burden (LSB) <10;n=15. Using the LCRI, n=15 were Long COVID+ (LC+) and n=39 were Indeterminate. The primary outcome, T-cell oxidative phosphorylation, did not differ between LC+ and Indeterminate nor by PROMIS scores. BMI and fat mass did not differ but T cell glycolytic activity was greater in those with LC+ vs Indeterminate. Lean mass and femoral BMD trended lower in the HSB vs LSB by both classifications. Prevalence of Type 2 diabetes did not differ by symptom scores, but HOMA-IR was higher and HOMA-B was lower in LC+ vs Indeterminate. SARS-CoV-2 viral RNA was not detectable in subcutaneous adipose tissue biopsies. CD26+ T cell number, and DPP-4 (CD26) activity were higher in the HSB and correlated significantly with symptom scores (r=0.52, p<0.01); plasma cytokines and stimulated T-cell cytokines did not differ by symptom group in either classification.

CONCLUSIONS
Individuals with Long COVID symptoms show subtle impairments in glucose tolerance, serum leptin, lean mass and enhanced T-cell DPP-4 activity. Participants with Long COVID have subtle changes in glucose metabolism that are not driven by SARS-CoV-2 virus in subcutaneous adipose tissue.

Web | DOI | PDF | Frontiers in Endocrinology | Open Access

 

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Some summary quotes from results and discussion (reordered) —

No differences were observed in the oxygen consumption rates in T cells of participants with LC+ vs Indeterminate, or by the PROMIS scoring. across all experimental conditions (n=42). Extracellular acidification rates stimulated with CD3/CD28 beads or the SARS-CoV2 peptide mix were not statistically significant between LC+ participants relative to Indeterminate individuals.

we found that the primary outcome, T cell oxidative phosphorylation, was not impaired in those with confirmed Long COVID symptoms vs those who were considered Indeterminate.

Notably, we report an increase in stimulated T cell extracellular acidification implying there may be a shift during activation of T cells, towards more rapid fuel utilization in symptomatic Long COVID participants.

However, we cannot exclude the possibility of metabolic rewiring during immune activation. The absence of differences in basal or stimulated oxygen consumption rates between individuals with LC+ versus Indeterminate indicates preserved mitochondrial respiratory competence, consistent with emerging reports that energetic fatigue in Long COVID does not uniformly reflect intrinsic mitochondrial failure.

No SARS-CoV-2 viral RNA or remnant was detected in any tissue compartment by qRT-PCR, including nasopharynx, blood, or subcutaneous adipose tissue. […] Consistent with those negative findings, RNAseq failed to identify any evidence of viral RNA in the subcutaneous adipose tissue of 18 biopsies analyzed using the LCRI classification

(CD26 = DDP-4.)

The analysis showed a significant accumulation of CD26 expressing lymphocytes in the LC+ group vs Indeterminate (p=0.001) and also for CD3/CD26 ratios comparing LC+ vs Indeterminate (p=0.002) but not by PROMIS scores.

DPP-4 enzyme activity was analyzed using frozen mononuclear cells. […] The peptidyl peptidase activity was significantly higher in the mononuclear cell fraction obtained from LC+ vs Indeterminate groups (p=0.001).

there was a strong correlation between T cell CD26 enzyme activity and symptom scores across the entire cohort.

in vitro stimulated T cells with the SARS-CoV-2 peptide from individuals with LC+ had enhanced glycolytic activation, greater numbers of CD26 + T cells and increased dipeptidyl peptidase (CD26) activity which correlated closely with symptom burden.

importantly, independent of fat mass, the high symptom group by each classification had greater leptin levels than those with few or any symptoms.

No evidence of inflammation.

we were unable to detect overt inflammatory signals either in the circulation or locally. For example bulk RNA seq from subcutaneous adipose tissue failed to reveal any signal of inflammatory genes. Similarly, circulating cytokines did not differ by symptom group, nor did in vitro stimulation of cytokine release, or histologic analysis of adipocytes.

In contrast to the lack of evidence for overt adipose tissue inflammation, there were indications that a chronic systemic immune response might be present. CD26+ T cell frequency as noted previously, was higher in participants with LC vs Indeterminate. CD26 (aka DPP-4) is a multifunctional enzyme highly expressed in many tissues, that is directly involved in the activation of T cells as a co-stimulatory molecule. It possesses dipeptidyl peptidase activity and can cleave GLP-1. In that vein, enzymatic activity of dipeptidyl peptidase in mononuclear cells was found to be higher in those individuals with high symptom scores. Theoretically, high DPP-4 enzyme activity in T cells could also lead to greater degradation of GLP-1, which could explain the subtle changes in glucose tolerance we noted.