Many patients who have survived a severe COVID-19 infection suffer from neurological abnormalities, such as impaired speech, memory loss or depression. So far little is known about what impact the coronavirus has on the human brain. A team of researchers from Saarland University and Stanford University has discovered that in patients with severe COVID-19, the SARS-CoV-2 virus can activate immune and barrier cells in the brain. The gene expression patterns found by the research team exhibit features similar to those found in individuals with cognitive disorders, schizophrenia and depression. The study has now been published in the world-renowned science journal ‘Nature’.
‘A number of studies have shown that viruses can cause inflammation of brain tissue. Whether COVID-19 is also able to induce such a response has been a subject of speculation. In our latest research we wanted to find out exactly what was happing at the cellular level in the brains of patients suffering from severe COVID-19,’ explains Andreas Keller, Professor of Clinical Bioinformatics at Saarland University, who has been studying this intriguing question with his team and with colleagues from Stanford University. They were able to collect tissue samples from eight patients who had died from COVID-19 and from 14 patients in a control, one of whom died from influenza and the others from non-viral causes. Walter Schulz-Schaeffer, Professor of Neuropathology at Saarland University, provided the tissue samples used in the study. Specifically, he extracted post-mortem tissue from the brains of the COVID-19 patients.
The tissue samples were taken from the frontal lobes of the cerebral cortex and from the choroid plexus, a tree-like network of capillaries, one of whose functions is the production of the cerebrospinal fluid. The cerebral cortex of the brain contains many different types of neurons and plays a key role in controlling our behaviour and our ability to concentrate and act. The choroid plexus also functions as an important barrier between two strictly separate physiological compartments: the circulating blood and the cerebrospinal fluid in the extracellular regions of the brain. ‘In Stanford, single-cell RNA-sequencing was used to analyse the active genes in every cell in the tissue samples separately. In total, we analysed around 65,000 cell nuclei from 30 brain samples. We found that a specific inflammatory reaction was triggered in the brain of the COVID-19 patients,’ explains Keller, who has been a visiting professor at Stanford since 2019.
Despite conducting systematic analyses, the researchers were unable to detect any genetic material from the SARS-CoV-2 virus in the brain, suggesting that the virus itself had not actually breached the blood-brain barrier. ‘However, the per-cell gene analyses showed us that there was a strong activation of immune cells in the brain tissue that are known as microglia. We were also able to detect activated T-cells (lymphocytes) that had migrated into the brain from the blood, further reinforcing the inflammatory milieu,’ says Keller. The team did not detect this type of inflammatory response of the brain’s neural tissue, known as neuroinflammation, in the patient who died from influenza or in any of the other patients in the control group.
‘We were also able to see other differences in the gene activation patterns in the neurons and in the glial cells and immune cells (the ‘microglia’) of the brain. Microglia are needed in order for neurons to function normally, but in certain situations they can also induce a chronic inflammatory response in the brain. The altered gene expression we observed in the neurons of patients who had died from COVID-19 are similar to the patterns that we find with other neurological or mental disorders, such as schizophrenia, depression or cognitive impairments,’ explains Fabian Kern, research associate in Andreas Keller’s group and co-lead author of the Nature publication, together with Andrew C. Yang from Stanford. The path to establishing this conclusion was a lengthy one. In order to identify the gene activation patterns, the bioinformatics expert had to automatically categorize the approximately 20,000 protein-coding genes of the human genome from every single cell and then compare those by cell type – generating around 1,3 billion data points. This procedure provided the research group with a sort of snapshot of the gene activity in each single cell from all the patients investigated in the study. ‘The quantity of data that we can nowadays generate with high-throughput, single-cell sequencing methods is so huge that it would be impossible to process without deploying sophisticated algorithms and state-of-the-art bioinformatics techniques,’ says Fabian Kern.
When the researchers first published their preliminary findings as a preprint in the autumn of 2020, little was known about these mechanisms in the cells of the brain. ‘We wanted to make our findings available to the scientific community as quickly as possible so that better therapies could be developed for patients suffering from severe COVID. It may be the case that the concentration problems (brain fog) and speech disruptions observed in people with post-acute / long COVID are related to these inflammatory processes in the brain. Future studies are required to examine this question in detail,’ says Kern.
In their research, the bioinformatics specialists in Saarbrücken are tackling questions related to other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. At the beginning of the year, Andreas Keller and Fabian Kern published a well-perceived study on prognostic biomarkers in Parkinson’s disease in Nature Aging. ‘To gain a better understanding of these molecular processes at the cellular level, we will soon conduct large-scale single-cell sequencing here in Saarland. This advanced technology will deliver a further boost to biomedical research at Saarland University,’ says Professor Andreas Keller.
This COVID-19 study was made possible by a unique interdisciplinary collaboration involving the Neurological Sciences at Stanford as well as the Bioinformatics and Neuropathology departments in Saarland. ‘It was only by collaborating and bringing together our complementary expertise that we were able to realize this research project in such a short timeframe,’ explains Andreas Keller. In addition to Professor Andreas Keller (joint last author together with Professor Tony Wyss-Coray, Stanford) and Professor Walter Schulz-Schaeffer, other members of Saarland University who contributed to the publication in Nature included Fabian Kern (co-lead author together with Andrew C. Yang, Stanford), Georges Schmartz, Tobias Fehlmann, Nicole Ludwig and Julian Stein.
Prof. Dr. Andreas Keller
Tel. +49 (0)681 302-68611
Fabian Kern, MSc
Tel. +49 (0)681 302-68610
Dysregulation of brain and choroid plexus cell types in severe COVID-19
https://www.scientificamerican.com/article/covid-can-cause-forgetfulness-psychos... - Article in Scientific American that references the Nature preprint
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