After infection with SARS-CoV-2, up to 10 percent of people in Germany go on to develop Long COVID. Symptoms can include persistent fatigue, difficulty concentrating, breathing problems, and neurological issues, and they may last for months or even years. The condition does not look the same in every patient, making it especially difficult to understand and treat.
“Long COVID is an extremely complex disease with various manifestations,” says Prof. Yang Li, head of the “Computational Biology for Individualized Medicine” department and director of CiiM. “How and to what extent Long COVID develops is still largely unknown. Figuratively speaking, we are unfortunately only looking at an extremely incomplete puzzle.”
Investigating Immune Cells in Long COVID Patients
To uncover more about what drives Long COVID, a research team led by Yang Li worked with colleagues including Prof. Thomas Illig (MHH) and Prof. Jie Sun (University of Virginia, USA), along with additional collaborators. Their goal was to identify biological mechanisms that could explain why symptoms persist.
The team focused on immune cells collected from Long COVID patients, using samples stored in MHH’s central biobank. “We examined the cells using a so-called single-cell multiomics approach. This allowed us to record the molecules’ status within a cell and gain insights into its cellular relationships,” explains Dr. Saumya Kumar, a CiiM scientist and the study’s first author.
In addition, the researchers measured levels of cytokines in blood plasma. These molecules act as signaling substances in the immune system and are often linked to inflammation. “The central and innovative approach of our study is to classify patient data according to the severity of the original COVID-19 disease,” says Yang Li. “This approach allowed us to capture the associated molecular differences in immune response across patients. Only in this way, clear molecular characteristics underlying the chronic symptoms of Long COVID could be identified.”
Key Immune Cell State Linked to Long COVID Symptoms
The researchers explored how immune cells change at the molecular level over time and whether specific markers are tied to symptoms like fatigue or breathing difficulties. Their large-scale data analysis pointed to a distinct molecular state in a type of white blood cell known as CD14+ monocytes, which play a key role in immune defense.
“With the help of single-cell analysis, we were able to zoom in on these cells. This revealed that monocytes with a specific molecular state (i.e. molecular profile), which we called “LC-Mo,” were particularly prevalent in Long COVID patients who had previously experienced mild to moderate COVID-19 disease,” says Saumya Kumar. “In addition, LC-Mo correlated with the severity of fatigue and respiratory symptoms and was associated with elevated cytokine levels in blood plasma, which are an indicator of inflammatory processes in the body.”
A New Clue in the Long COVID Puzzle
The identification of LC-Mo provides an important new lead in understanding Long COVID. While researchers have not yet determined exactly how this immune cell state contributes to the condition, it opens the door to future studies focused on genetic risk factors and personalized treatment approaches.
“Its exact place in the pathogenesis of Long COVID has yet to be determined, but it offers exciting starting points for further studies, for example, with regard to genetic risk factors or individualized medicine,” says Yang Li. “If we can gain a better understanding of the background to the development of Long COVID, it will also help us to better understand the development of possible late or long-term consequences of other infectious diseases.”
The research was funded by an ERC Starting Grant (ModVaccine), the COVID-19 Research Network of Lower Saxony (COFONI) and the Lower Saxony Centre for AI & Causal Methods in Medicine (CAIMed), both supported by the Lower Saxony Ministry of Science and Culture (MWK), as well as the Federal Ministry of Research, Technology and Space (BMFTR).