A network under the leadership of the Charité is researching the causes and mechanisms of the disease.
After an infectious disease, most people recover without further consequences. Others, however, feel persistently exhausted, and even the smallest effort, such as turning over in bed, becomes an effort. Symptoms like this have come into the limelight with Long-COVID and Post-COVID Syndrome. Long-term consequences after infections have been known for many years. They have hardly been researched. An interdisciplinary consortium led by scientists at the Charité – Universitätsmedizin Berlin is now working to clarify what underlies the complex neuroimmunological disease myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), also known as post-infectious fatigue syndrome, at the molecular level. The Federal Ministry of Education and Research (BMBF) is funding the work with about two million euros over the next three years.
The long-term consequences of the COVID-19 disease caused by the SARS coronavirus type 2 are becoming increasingly apparent as the pandemic progresses. The number of people who are permanently disabled and in need of treatment is increasing, and with it the need for robust knowledge about the possible late and long-term effects observed in connection with COVID-19 and other infectious diseases. ME/CFS is a serious, usually lifelong disease with varying degrees of physical and mental symptoms. The most common symptoms are weakness and fatigue, muscle pain, headaches, intestinal problems, dizziness, sensitivity to stress and stimuli, rapid heartbeat or fluctuations in blood pressure. Typically, deterioration occurs as a result of even minor exertion, known as post-exertional malaise. In the majority of patients, the disease begins after a viral infection. Various pathogens are now known as triggers, including herpes viruses such as the Epstein-Barr virus, dengue or influenza viruses. After the SARS pandemic in 2002 and 2003, some of those infected developed ME/CFS. In the current COVID 19 pandemic, it appears that a subgroup of the long COVID sufferers also developed ME/CFS. Even before the pandemic began, experts estimated that about 300,000 people in Germany alone, including about 40,000 under the age of 18, suffer from the chronic disease. About half of the predominantly younger and female patients are so ill that they can no longer work. The most severely affected are bedridden and no longer able to care for themselves. While it was assumed for a long time that it was a psychosomatic disease, the World Health Organisation (WHO) classified ME/CFS as a neurological disease as early as 1969.
The exact mechanisms that lead to the disease are still unclear. Recent studies point to autoimmune processes and a dysregulation of the autonomic nervous system and cellular energy metabolism. However, there is still a lack of approved and effective treatment options, as well as reliable biomarkers, measurable values in blood or serum that can be used to diagnose the disease. The current project, called IMMME – IMune Mechanism of ME, aims to change this. Prof. Dr. Carmen Scheibenbogen, acting director of the Institute of Medical Immunology at the Charité Campus Virchow-Klinikum, has been working on the clinical picture of post-infectious chronic fatigue syndrome (ME/CFS) for many years. She heads the Immunodeficiency Outpatient Clinic as well as the Fatigue Centre at the Charité and now also the interdisciplinary research network IMMME. “I am very happy about the funding of this collaborative project and about being able to work on it with a team of experts in ME/CFS, COVID-19 and the immune system. It comes at the right time, because the topic of post-infectious diseases has taken on a new dimension as a result of the pandemic,” says Prof. Scheibenbogen. “It is the first time that a research network on ME/CFS is now being funded in Germany.”
So what leads to the long-term neuroimmunological disease, for which so far only individual symptoms can be treated, but not the actual cause? The Epstein-Barr virus, which causes glandular fever, has already been proven to trigger autoimmune reactions. A similar risk for autoimmunity exists after COVID-19, the research team suspects. While in healthy people autoantibodies contribute to the control of important processes, they can change their function after infections and lead to the development of autoimmune diseases. In the case of ME/CFS, scientists led by Prof. Scheibenbogen and other groups were able to detect autoantibodies against so-called G-protein-coupled receptors, key proteins in signal transduction, which are associated with the severity of symptoms. Among them are those directed against stress receptors and linked to major symptoms such as fatigue and muscle pain, and also those associated with reduced cognitive abilities. The role played by individual autoantibodies and cross-reacting viral antibodies, and the way in which signalling pathways are affected by possible cross-reactions, is being investigated by the new research network in five sub-projects. The basis for the comprehensive analyses are well-characterised biological samples from a common ME/CFS biobank. Different parameters are collected within the individual projects and evaluated together in a database. The aim of the work is to create a systematic, comprehensive basis for diagnostic markers for the first time. In particular, the researchers hope that they will succeed in identifying structures that serve as a basis for targeted therapy approaches for the autoimmune disease.
The hypothesis of Prof. Scheibenbogen’s team is that some of the autoantibodies are altered in their structure and bind to certain receptors in such a way that incorrect information in the cells leads to malfunctions in immunological, regulatory or metabolic processes. One focus of the work is therefore on details in the binding behaviour of autoantibodies and the corresponding receptors. Rheumatology and clinical immunology at the University Hospital Lübeck contribute to the studies with molecular analyses. Experts from the German Centre for Neurodegenerative Diseases (DZNE), Bonn, in close cooperation with Prof. Dr. Leif E. Sander, Director of Infectiology at the Charité Medical Clinic with a focus on Infectiology and Pneumology, are investigating different immune cell types using RNA sequencing at the single cell level to identify possible changes in their signalling pathways and potential biomarkers. A team at the University Hospital Würzburg is dedicated to the causes of the altered energy metabolism within the cell in ME/CFS, while a team at Charité and University Hospital Munich is investigating antibodies against the Epstein-Barr virus and cross-reactions with the body’s own structures for comparison. A team at Charité is collecting and analysing data from control groups of patients with multiple sclerosis and other autoimmune diseases.