Targeting post-COVID and ME/CFS with single-cell transcriptome analyses

At present, the COVID pandemic has lost some of its horror: there are vaccines that generally provide good protection against severe courses, and also against acute infections there are now approved drugs. However, the picture looks quite different for the diseases usually summarized under the names Long-COVID and Post-COVID, which are often also associated with the so-called myalgic encephalomyelitis with chronic fatigue syndrome (ME/CFS). To date, no real therapy exists for these syndromes, and research is only slowly uncovering their causes and mechanisms.

A new National Clinical Study Group now wants to investigate whether drugs already approved for other diseases and available on the market are effective against ME/CFS. The study is funded by the German Federal Ministry of Education and Research with 10 million euros and brings together the expertise of various specialized study partners.

Investigation at the single cell level

Also contributing is a research unit on systems medicine at the DZNE, led by Marc Beyer, Anna Aschenbrenner and Joachim L. Schultze: using state-of-the-art laboratory technology, the Bonn researchers are investigating how ill and healthy cells differ at the cellular and molecular biological level - and what drugs actually do here. For their research project, the group is looking at cells in the blood of people suffering from ME/CFS: before, during and after treatment with various drugs (which are currently used and have been approved in particular to combat inflammation, circulatory disorders and autoantibodies, i.e. antibodies that attack certain of the body's own proteins).

The catchword here is high-throughput single-cell transcriptome analysis. Using this highly sensitive method, the scientists in the laboratories on the Venusberg in Bonn examine whether the administered drugs change the transcriptome of the cells, and if so: how exactly. To this end, many different cell types from blood samples of the study participants are first isolated and separated. Next-generation sequencing and computer-assisted analyses then make it possible to simultaneously measure the activity of thousands of genes of a cell and see how it responds to certain treatments. “Single-cell analyses allow us to get an accurate picture of a cell's condition. And we can also quickly tell whether an administered drug actually works at this level," says Marc Beyer, working group leader at the DZNE and co-leader of the biomarker platform project, summing up key advantages of the method.

Should they find that changes at the transcriptome level of the cells correlate with clinical observations, conclusions can be drawn about the drug's effective mechanisms against ME/CFS. In addition, such empirically evident results can be used to objectify patient-reported and physician-observed improvements.

Wanted: unambiguous biomarkers

In order to actually be sure that a given medication leads to recovery, it is also useful to know what exactly distinguishes diseased cells from healthy ones - i.e. what the transcriptome of a healthy cell looks like, which changes indicate a ME/CFS disease, and whether a cell changes back from a diseased to a healthy state. Up to now, this has not been possible in ME/CFS based on lab results; diagnoses are only made from the clinical appearance of the patient.

Biomarkers, i.e. specific signals for the disease that can be detected in the blood, would therefore be very helpful. If in a significant number of patients the clinical symptoms correlate with certain transcriptome patterns, such transcriptome patterns could be a biomarker. These are also being searched for at DZNE, as part of another study project led by Anna Aschenbrenner: "The sequencing of single-cell transcriptomes generates very large, complex volumes of data. In searching for patterns typical of ME/CFS, we are therefore using advanced, AI-assisted analysis methods. We thus hope to be able to establish a connection between clinical symptoms and events at the cellular level," says Aschenbrenner, explaining the experimental approach. A long-term goal could be to develop test procedures by which physicians or laboratories can read out these biomarkers and use them to make a diagnosis.

Joachim L. Schultze, head of the Systems Medicine research area at DZNE, is convinced of the lasting impact of DZNE's contribution to the study - and beyond: "With single-cell analyses, we can now get a much more precise picture of the exact disease mechanisms and the active principles of drugs derived from them. And we can continually refine this picture through further research. The knowledge we gain through our work for the National Clinical Study Group on Long COVID and ME/CFS will first benefit the people who suffer from these diseases. In the medium and long term, however, they also form a basis for further advances in precision medicine and in the diagnosis and treatment of many other diseases."

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