Research Summary

Biomarkers Reveal Immune Dysregulation in Long COVID

Miranda Manier, BA

Key Highlights

  • Long COVID is associated with diminished neutralizing antibody activity despite similar total spike-specific IgG titers.
  • Subtle differences in co-inhibitory receptor expression (PD-1 and TIM-3) were observed on CD8+ T cells in patients with long COVID.
  • Plasma proteomic signatures in long COVID correlate with breathlessness and highlight pathways of apoptosis and inflammation.
  • These findings suggest persistent antigen exposure and immune dysregulation in long COVID.

A new study offers an exploration of the immunological and proteomic signatures that define long COVID, aiming to uncover biomarkers that could illuminate the pathogenesis of this persistent, multisystemic condition.

The April 2025 study published in Nature Immunology found that, despite similar total SARS-CoV-2 spike-specific IgG titers, individuals with long COVID exhibited significantly diminished neutralizing antibody activity compared with healthy convalescent individuals. Immune cell lineage composition and antiviral T cell immunity showed minimal differences between the groups. However, individuals with long COVID demonstrated increased expression of co-inhibitory receptors, notably PD-1 and TIM-3, on SARS-CoV-2 nonspike-specific CD8+ T cells, indicating immune dysregulation. Unique plasma biomarker signatures linked with breathlessness were also identified, reflecting dysregulated pathways associated with apoptosis, inflammation, lung injury, and platelet activation.

This study aimed to address the complex and still poorly understood nature of long COVID. Despite mounting evidence that immune dysregulation, ongoing inflammation, and viral persistence may underlie the persistent symptoms of long COVID, prior investigations have yielded conflicting findings, often hampered by cohort variability and limited molecular resolution. Gao Y and colleagues harnessed multidimensional immune profiling and high-throughput plasma proteomics across geographically distinct cohorts to address these uncertainties and identify consistent biomarkers.

The researchers recruited healthy convalescent individuals and individuals with long COVID from both the United Kingdom and Sweden. Using advanced flow cytometry, they characterized immune cell populations and antigen-specific T cell responses, while plasma samples were analyzed using an affinity-based proteomics platform. These data were integrated with clinical symptom scores, particularly focusing on breathlessness, a hallmark feature of long COVID.

The detailed results revealed comparable distributions of major immune cell populations and antigen-specific T cell responses across groups. Healthy convalescent individuals demonstrated higher SARS-CoV-2 neutralizing activity than individuals with long COVID, despite equivalent spike-specific IgG titers. Subtle but consistent increases in co-inhibitory receptor expression, especially PD-1 and TIM-3, were observed on SARS-CoV-2 nonspike-specific CD8+ T cells in individuals with long COVID. Plasma proteomics identified a distinctive biomarker signature linked to breathlessness, centered around proteins such as CCL3, CD40, IL-18, and IRAK1, which are associated with apoptotic and inflammatory pathways, cell cycle progression, and platelet activation. These findings suggest that long COVID involves a persistent immune imbalance and circulating protein markers that could serve as potential diagnostic or therapeutic targets.

Limitations of the study include differences in sampling times between healthy convalescent individuals and long COVID cases, as well as the interpretive challenges of linking plasma biomarkers directly to localized tissue pathology. Further studies are needed to validate the tissue-specific relevance of these findings.

“These results provide a mechanistic framework to unravel the complex etiology and pathogenesis of ongoing symptomatic disease triggered by infection with SARS-CoV-2,” the study authors concluded.

Reference:
Gao Y, Cai C, Adamo S, et al. Identification of soluble biomarkers that associate with distinct manifestations of long COVID. Nat Immunol. 2025;26,692–705. doi: 10.1038/s41590-025-02135-5