Study results could contribute to more effective treatment
by Dr. Marcus Neitzert
(21.01.2021) According to current studies, the COVID-19 disease caused by the SARS-CoV-2 coronavirus comprises at least five different variants. These differ in how the immune system reacts to the infection. Researchers from the German Center for Neurodegenerative Diseases (DZNE) and the University of Bonn present these findings together with other experts from Germany, Greece and the Netherlands in the scientific journal “Genome Medicine”.
An infection with SARS-CoV-2 can have different effects: Many people affected seem not to notice the virus attack at all. In other cases, the effects can range from flu-like symptoms and neurological disorders to severe and even life-threatening pneumonia. “The division of COVID-19 into mild and severe courses falls short. The disease is much more diverse and, of course, you want a therapy that is tailor-made for each person affected. What helps one may be ineffective for another, ”says Dr. Anna Aschenbrenner, scientist at the LIMES Institute of the University of Bonn, who also belongs to the DZNE’s systems medicine department.
“In this respect, it makes sense to want to understand what these differences are based on. If you can fix it to scientific criteria and assign those affected accordingly, this increases the chances of effective treatment. We therefore looked at the immune system. Because many studies meanwhile indicate that its reaction to the infection with SARS-CoV-2 plays a decisive role in the course of COVID-19 “, says Dr. Aschenbrenner, who is a member of the Excellence Cluster” ImmunoSensation “at the University of Bonn.
Against this background, a team led by Dr. Anna Aschenbrenner, together with colleagues from Germany and abroad, tested the blood of people with and without COVID-19. The samples came from a total of 95 people from Bonn, Athens and Nijmegen. The investigations were carried out in cooperation with the “German COVID-19 OMICS Initiative” (DeCOI) – a nationwide association of universities and research institutions. In addition to the DZNE and the University of Bonn, the University Hospital was also involved in Bonn. Foreign partners were the Attikon University Hospital, the Sotiria Hospital in Athens and the Radboud University Medical Center in Nijmegen in the Netherlands.
The so-called transcriptome of the immune cells in the blood was determined for each patient, and enormous amounts of data were evaluated using bioinformatics methods. Using the molecular fingerprint generated in this way, the researchers were able to identify which genes were switched on or off within the immune cells. Such signatures of gene activity – also called “expression patterns” – provide information about the condition of cells and thus about their properties and functions, which can change depending on the situation.
Interestingly, the blood count obtained in this way was largely determined by the “neutrophil” family: They are the most common of the so-called white blood cells and are at the forefront of the immune response chain. These cells are mobilized very early to fight off infections. They influence the production of antibodies and also other cells that contribute to immunity.
“First of all, it must be noted that the expression patterns of immune cells in people with COVID-19 differ fundamentally from those in healthy people. The gene activity that we can read out in the blood is greatly changed. But there are also striking differences among patients. On this basis we have identified five different groups. We’re talking about molecular phenotypes, ”says Dr. Thomas Ulas, expert in bioinformatics at the DZNE. “Two of them stand for serious disease courses. The other three show more moderate symptoms. ”The classification was based solely on the transcriptome data. Only in retrospect was it checked which clinical courses the individual phenotypes corresponded to.
COVID-19 is special
The researchers used their findings to compare COVID-19 with other diseases and also with data from healthy people. For this purpose, they were able to access data from the “Rhineland Study” – a population study by the DZNE in the Bonn area – as well as scientific databases. A wide range of diseases was taken into account for the comparison: including viral infections such as influenza, infections with HIV and Zika, bacterial infections such as tuberculosis and bacterial sepsis, and inflammatory diseases such as rheumatoid arthritis. “All five COVID-19 phenotypes differ from the other diseases that we examined,” says Ulas, summing up the results. “COVID-19 apparently has a unique biology, which is reflected in the gene activity of immune cells in the blood. In this respect, expression analysis could be used to diagnose COVID-19. That would be an alternative or a supplement to current procedures. “
Search for active ingredients
The scientists also looked for possible drugs against COVID-19. To do this, they used the effects of around 900 approved drugs on the expression patterns of cells, which are stored in databases. “We calculated which pharmaceuticals could counteract the changed gene activity profiles of the individual COVID-19 phenotypes,” says Aschenbrenner, describing the procedure. On this basis, drug candidates for the therapy could be identified. “As early as April last year, for example, we calculated a potential effectiveness for dexamethasone and baricitinib in one of the patient groups we identified with a severe course. It must be clearly stated that these types of analyzes are not recommendations for treatment. However, they do offer starting points for therapy development, which must then be checked in appropriate studies. In the case of dexamethasone and baricitinib, our predictions turned out to be correct. This is an indication of the strength of our approach of using blood transcriptomes to better characterize and classify patients. “
(Originalpublikation: Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients, Aschenbrenner et al., Genome Medicine (2021), DOI: 10.1186/s13073-020-00823-5;