Identification of soluble biomarkers that associate with distinct manifestations of long COVID, 2025, Gao, Buggert, Peluso et al

Now published: post with link here

*******
Identification of soluble biomarkers that associate with distinct manifestations of long COVID

Marcus Buggert, Yu Gao, Curtis Cai, Sarah Adamo, Elsa Biteus, Habiba Kamal, Lena Dager, Kelly Miners, Sian Llewellyn-Lacey, Kristin Ladell, Pragati Sabberwal, Kirsten Bentley, Jinghua Wu, Mily Akhirunnesa, Samantha Jones, Per Julin, Christer Lidman, Richard Stanton, Helen Davies, Soo Aleman, David Price, Paul Goepfert, Steven Deeks, Michael Peluso

Abstract
Long COVID is a heterogeneous clinical syndrome of uncertain etiology triggered by infection with SARS-CoV-2. We employed ultrasensitive approaches to profile the immune system and plasma proteome in healthy convalescent individuals and patients with long COVID.

Symptomatic disease was not consistently associated with quantitative differences in immune cell lineage composition or antiviral T cell immunity. Healthy convalescent individuals nonetheless exhibited higher titers of neutralizing antibodies against SARS-CoV-2 than patients with long COVID, and extensive phenotypic analyses revealed a subtle increase in the expression of some coinhibitory receptors, most notably PD-1 and TIM-3, among SARS-CoV-2 nonspike-specific CD8+ T cells in patients with long COVID.

We further identified a plasma biomarker signature of disease linking breathlessness with apoptotic inflammatory networks centered on the hub protein TRAF2 and dysregulated pathways associated with lung injury, cell cycle progression, and platelet activation, which could potentially inform the diagnosis and treatment of long COVID.

Link | PDF (Preprint)

 

HAVCR2 (TIM-3) on Wikipedia

The page also lists some ligands that bind to TIM-3, a couple of which rang a bell.

It lists CEACAM1. We've seen upregulation of CEACAM3, though I'm not sure how related they are.

Edit: CEACAM1 was upregulated in long COVID but not ME/CFS in the quoted post. CEACAM3 was upregulated in both conditions.

 

From reference 41 in Wikipedia page above:

Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection, 2010, Hyun-Tak Jin et al

 

The paper has now been published

https://www.nature.com/articles/s41590-025-02135-5

 

Press release from Karolinska Institutet:
Long COVID biomarkers found - associated with respiratory problems

Quote:
“The proteins were mainly found in patients with Long COVID and severe respiratory problems,” says Dr Buggert. “This is a biomarker pattern that we know to be linked to inflammatory signal pathways involved in cell death and lung damage and that has also been observed in other patient groups with severe pulmonary disorders.”

https://via.tt.se/pressmeddelande/3...piratory-problems?publisherId=3236933&lang=sv

 

https://www.nature.com/articles/s41590-025-02135-5

• Article
• Open access
• Published: 30 April 2025

Identification of soluble biomarkers that associate with distinct manifestations of long COVID

• Yu Gao,
• Curtis Cai,
• Sarah Adamo,
• Elsa Biteus,
• Habiba Kamal,
• Lena Dager,
• Kelly L. Miners,
• Sian Llewellyn-Lacey,
• Kristin Ladell,
• Pragati S. Amratia,
• Kirsten Bentley,
• Simon Kollnberger,
• Jinghua Wu,
• Mily Akhirunnesa,
• Samantha A. Jones,
• Per Julin,
• Christer Lidman,
• Richard J. Stanton,
• Paul A. Goepfert,
• Michael J. Peluso,
• Steven G. Deeks,
• Helen E. Davies,
• Soo Aleman,
• Marcus Buggert &
• David A. Price

Nature Immunology volume 26, pages692–705 (2025)Cite this article

• Metricsdetails
  

Abstract

Long coronavirus disease (COVID) is a heterogeneous clinical condition of uncertain etiology triggered by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Here we used ultrasensitive approaches to profile the immune system and the plasma proteome in healthy convalescent individuals and individuals with long COVID, spanning geographically independent cohorts from Sweden and the United Kingdom.

Symptomatic disease was not consistently associated with quantitative differences in immune cell lineage composition or antiviral T cell immunity.

Healthy convalescent individuals nonetheless exhibited higher titers of neutralizing antibodies against SARS-CoV-2 than individuals with long COVID, and extensive phenotypic analyses revealed a subtle increase in the expression of some co-inhibitory receptors, most notably PD-1 and TIM-3, among SARS-CoV-2 nonspike-specific CD8+ T cells in individuals with long COVID.

We further identified a shared plasma biomarker signature of disease linking breathlessness with apoptotic inflammatory networks centered on various proteins, including CCL3, CD40, IKBKG, IL-18 and IRAK1, and dysregulated pathways associated with cell cycle progression, lung injury and platelet activation, which could potentially inform the diagnosis and treatment of long COVID.

 

https://www.eurekalert.org/news-releases/1082365

News Release 30-Apr-2025
Long COVID biomarkers found – associated with respiratory problems
Peer-Reviewed Publication

Karolinska Institutet


Researchers at Karolinska Institutet have identified biomarkers in the blood associated with symptoms of long COVID, particularly severe respiratory disorders. The discovery can pave the way for future diagnosis and treatment. The results are published in the top-ranking scientific journal Nature Immunology.

Long COVID, also known as Post COVID, is a condition characterised by persistent symptoms of previous COVID-19. A new study from Karolinska Institutet, Sweden, and Cardiff University, UK, led by Marcus Buggert, docent at the Department of Medicine, Karolinska Institutet (Huddinge), has identified a set of proteins in the blood of people with Long COVID.

“The proteins were mainly found in patients with Long COVID and severe respiratory problems,” says Dr Buggert. “This is a biomarker pattern that we know to be linked to inflammatory signal pathways involved in cell death and lung damage and that has also been observed in other patient groups with severe pulmonary disorders.”

Detailed analysis of blood samples

Severe and permanent symptoms of acute breathlessness is one of the most common and most typical symptoms of Long COVID. The researchers also studied samples from a group of patients that had recovered from their previous COVID-19 and who had, interestingly, none of these proteins in their blood.

The finding was based on a detailed analysis of blood samples from independent patient groups in Sweden and the UK, something that had not been done before.

All 265 patients who participated in the study had contracted COVID-19 during the early days of the pandemic when no vaccine was yet available. Using advanced techniques, the researchers measured thousands of proteins in the blood plasma, which they related to the patients’ symptoms. They also used flow cytometry to conduct immunological analyses.

“By identifying the proteins that are elevated in affected patients, we’re creating a platform from which to develop diagnostic tools and new targeted therapies,” Dr Buggert says. “This is especially important since there are no specific biomarkers and treatments for Long COVID.”

Symptom biology

The results of the study expose the underlying biological processes that can cause certain patients to experience severe symptoms long after previous COVID-19.

The next step in the research is to understand what underpins this pattern by studying lung and gastrointestinal tissue. In doing so, the researchers hope to locate the source of the identified proteins and find if there is any remaining inflammation or tissue damage in specific organs of patients with Long COVID.

The study was funded by the PolyBio Research Foundation, the Swedish Research Council, SciLifeLab/KAW National COVID-19 Research Program, the Knut and Alice Wallenberg Foundation and Karolinska Institutet. Some of the co-authors receive consultancy and lecture fees from pharmaceutical companies, but they are unconnected to this study.

Publication: “Identification of soluble biomarkers that associate with distinct manifestations of long COVID”, Yu Gao, Curtis Cai, Sarah Adamo, Elsa Biteus, Habiba Kamal, Lena Dager, Kelly L. Miners, Sian Llewellyn-Lacey, Kristin Ladell, Pragati S. Amratia, Kirsten Bentley, Simon Kollnberger, Jinghua Wu, Mily Akhirunnesa, Samantha A. Jones, Per Julin, Christer Lidman, Richard J. Stanton, Paul A. Goepfert, Michael J. Peluso, Steven G. Deeks, Helen E. Davies, Soo Aleman, Marcus Buggert & David A. Price, Nature Immunology, online 30 April 2025, doi: 10.1038/s41590-025-02135-5.

Journal
Nature Immunology

DOI
10.1038/s41590-025-02135-5

Method of Research
Observational study

Subject of Research
People

Article Title
Identification of soluble biomarkers that associate with distinct manifestations of long COVID

Article Publication Date
30-Apr-2025