Researchers have identified a distinct immune cell state that may help explain persistent fatigue and respiratory impairment in patients with long COVID, according to a recent study. The findings linked systemic immune dysfunction to pulmonary pathology through a specific transcriptional program in circulating monocytes.
Long COVID affects an estimated 10% to 20% of patients who have experienced SARS-CoV-2 and can involve symptoms lasting for years, including fatigue, dyspnea, and cognitive dysfunction. Despite extensive research, the biological mechanisms underlying these persistent symptoms have remained unclear.
In the study, the researchers integrated single-cell multiomic profiling, plasma cytokine measurements, and functional immune assays across multiple independent cohorts. They identified a circulating CD14-positive monocyte transcriptional state associated with long COVID that they termed LC-Mo. This state was enriched in those who developed long COVID following mild to moderate acute infections.
“This state coincided with persistent elevation of circulating cytokines, indicating systemic inflammation,” wrote Saumya Kumar, of the Centre for Individualised Infection Medicine at the Helmholtz Centre for Infection Research and Hannover Medical School in Germany, and colleagues. Plasma levels of the cytokines CCL2 and CXCL11 as well as the chemical messenger tumor necrosis factor (TNF) remained elevated for up to 9 months postinfection, supporting ongoing immune activation.
The LC-Mo state was characterized by increased signaling through transforming growth factor beta and WNT–beta-catenin pathways and was associated with clinical severity.
According to the researchers, patients with long COVID who had a high proportion of MC4 exhibited greater fatigue compared with those with LC with a low proportion of MC4, which was the monocyte cluster that defined the LC-Mo transcriptional program.
Higher LC-Mo expression was also associated with poorer respiratory outcomes. The researchers reported a negative correlation between LC-Mo abundance and arterial oxygen levels. In bronchoalveolar lavage samples from patients with severe respiratory symptoms, LC-Mo–like macrophages demonstrated a profibrotic gene expression profile. As a result, the researchers suggested a mechanistic link between systemic immune alterations and lung remodeling.
Functional immune testing further showed impaired antiviral responses. For instance, the patients with high LC-Mo expression demonstrated reduced interferon signaling following ex vivo immune stimulation, indicating compromised immune regulation.
In addition, epigenetic analyses revealed that the LC-Mo state was driven by transcription factors associated with inflammation and fibrosis, including AP-1 and NF-κB1. These pathways have been implicated previously in chronic inflammatory and fibrotic diseases.
"[O]ur findings define a pathogenic monocyte transcriptional state linking systemic immune dysfunction to persistent long COVID disease, providing mechanistic insights and potential therapeutic targets," the study authors said.
While the study established strong associations between immune dysregulation and clinical symptoms, the researchers emphasized that causality remains to be determined. They indicated that further studies will be needed to assess whether targeting this monocyte state could improve outcomes among patients with long COVID.
Disclosures: Co–study author Mihai G. Netea reported being the founder of Biotrip, Salvina, TTxD and Lemba. Another study author received fees for consultations or lectures from 35Pharma, Acceleron, Actelion, Aerovate, AOP Health, Bayer, Ferrer, Gossamer, Inhibikase, Janssen, Keros, MSD, and Novartis. No other conflicts of interest were reported.
Source: Nature Immunology