Immune cell communication networks and memory CD8+ T cell signatures sustaining chronic inflammation in COVID-19 and Long COVID, 2025, Liu et al.

[Chandelier]

Frontiers | Immune cell communication networks and memory CD8+ T cell signatures sustaining chronic inflammation in COVID-19 and Long COVID

BackgroundCOVID-19, including its post-acute sequelae (Long COVID), is increasingly recognized as involving persistent immune dysregulation and chronic infla...

www.frontiersin.org

Spoiler: Authors

Liu H, Xu Z, Karsidag I, Wang P and Weng J

Background: COVID-19, including its post-acute sequelae (Long COVID), is increasingly recognized as involving persistent immune dysregulation and chronic inflammation. Severe and prolonged disease states are often accompanied by sustained cytokine release, immune cell exhaustion, and ongoing cell-cell communication that shapes the inflammatory milieu. Among immune subsets, CD8+ T cells play a central role in antiviral defense, yet the molecular mechanisms linking their dysfunction to prolonged inflammation remain incompletely understood.

Methods: We analyzed 73,110 peripheral blood mononuclear cells (PBMCs) from individuals across four disease states (Healthy, Exposed, Infected, and Hospitalized) using single-cell RNA sequencing. Immune cell subsets were annotated, and T cell heterogeneity was profiled. Cytokine and inflammatory scores were calculated to assess immune activation. Differentially expressed genes (DEGs) underwent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Cell-cell communication was evaluated to map ligand-receptor networks. Additionally, nine machine learning models were trained on a bulk RNA-seq cohort, and the SHapley Additive exPlanations (SHAP) framework was applied to interpret key predictive genes.

Results: Progressive disease severity was associated with a decline in T cell proportions, enrichment of pro-inflammatory myeloid cells, and elevated cytokine expression, particularly IL-32. Memory CD8+ T cells showed increased exhaustion and inflammatory scores while maintaining a central position in MHC-I-mediated communication networks. Persistent activation of immune and metabolic pathways, including antigen presentation and oxidative phosphorylation, was observed in prolonged disease states. Seven genes (RPS26, RPS29, RPL36, RPL39, RPS28, RPS21, and CD3E) were identified as strong predictors of chronic immune dysregulation, with the XGBoost model achieving the highest AUC. SHAP analysis confirmed their contributions to disease classification.

Conclusion: This study maps the immune landscape of COVID-19 and Long COVID at single-cell resolution, revealing that persistent immune cell communication, particularly involving memory CD8+ T cells, may sustain chronic inflammation beyond the acute phase. The identified molecular signatures offer potential biomarkers and therapeutic targets for mitigating post-viral inflammatory syndromes.

 

[Jonathan Edwards]

Usual business of presenting interpretation rather than data.
I am getting behind with reading any of these in full.

 

[V.R.T.]

while maintaining a central position in MHC-I-mediated communication networks

What does this mean?

Seven genes (RPS26, RPS29, RPL36, RPL39, RPS28, RPS21, and CD3E) were identified as strong predictors of chronic immune dysregulation,

Have we seen any of these genes before?

 

[V.R.T.]

We profiled 73,110 high-quality PBMCs from eight individuals, constructing immune landscapes across four clinical groups: Healthy, Exposed, Infected, and Hospitalized.

Eight individuals? Is that normal for this type of study?

Importantly, our findings have direct implications for understanding chronic inflammation in post-viral syndromes such as Long COVID. The persistence of elevated cytokine expression, enrichment of pro-inflammatory myeloid cells, and sustained MHC-I-mediated interactions involving memory CD8+ T cells suggest that the immune system remains in a state of low-grade but continuous activation well beyond the acute infection.

Sounds like they only studied eight acute covid patients and extrapolated about long covid from there? Is this a valid approach?

Our model aligns with emerging evidence that sustained antigen presentation and maladaptive cross-talk between adaptive and innate immune compartments underlie long-term symptoms. Therapeutically, targeting key communication nodes—through modulation of ligand-receptor pathways or restoration of T cell metabolic balance—may help disrupt this cycle

This sounds like the sort of vicious cycle and the sort of treatment we have been speculating about on here, but do the data they provide actually give us any evidence for this conclusion?

I may have missed stuff due to brain fog but I am confused by the gap between sample size and methods and the conclusion.

 

[SNT Gatchaman]

Agree, and they're not looking at LC patients. Instead working with the assumption that —

This excessive and sustained inflammatory response is increasingly recognized as a key contributor to chronic immune dysregulation, driving disease progression and multi-organ damage in Hospitalized patients.