An electron microscope image (ultra-thin section, artificially colored) shows a section of a ciliated cell in the olfactory mucous membrane. A large number of intact SARS-CoV-2 particles (red) are found both in the cell and in cellular processes. Yellow: cinema cilia.
Photo: Michael Laue / RKI & Carsten Dittmayer / Charité
A research team out Charity – – University Medicine Berlin examined the mechanisms by which the novel coronavirus can reach the brains of patients with COVID-19 and how the immune system reacts to the virus as soon as it does so. The results, which show that SARS-CoV-2 reaches the brain via nerve cells in the olfactory mucosa, were published in Nature Neuroscience *.
For the first time, researchers were able to create electron microscopic images of intact coronavirus particles in the olfactory mucosa.
It is now known that COVID-19 is not just a respiratory disease. SARS-CoV-2 affects not only the lungs, but also the cardiovascular system, the gastrointestinal tract and the central nervous system.
More than one in three people with COVID-19 report neurological symptoms such as loss or change in their sense of smell or taste, headache, fatigue, dizziness and nausea. In some patients, the disease can even lead to stroke or other serious illnesses. So far, researchers had suspected that these manifestations must be caused by the virus that invades and infects certain cells in the brain. But how does SARS-CoV-2 get there? Under the joint direction of Dr. Helena Radbruch from CharityThe Department of Neuropathology and the Director of the Department, Prof. Dr. Frank Heppner, a multidisciplinary research team, have now followed how the virus gets into the central nervous system and then enters the brain.
The immunofluorescence staining shows a nerve cell (pink) in the olfactory mucosa that was infected with SARS-CoV-2 (yellow). Supporting (epithelial) cells appear blue.
Photo: Jonas Franz / Göttingen University Medical Center
As part of this research, experts from the fields of neuropathology, pathology, forensic medicine, virology and clinical care examined tissue samples from 33 patients (mean age 72 years) who had both died Charity or the Göttingen University Hospital after completing COVID-19.
Using the latest technology, the researchers analyzed samples from the olfactory mucosa of deceased patients and from four different brain regions. Both the tissue samples and various cells were tested for SARS-CoV-2 genetic material and a “spike protein” located on the surface of the virus.
The team provided evidence of the virus in various neuroanatomical structures that connect the eyes, mouth, and nose to the brain stem. The olfactory mucosa showed the highest viral load. With the help of special tissue stains, the researchers were able to create electron microscopic images of intact coronavirus particles in the olfactory mucosa for the first time. These have been found both in nerve cells and in processes that extend from nearby supporting cells (epithelial cells). All samples used for this type of image-based analysis must be of the highest quality. To ensure this, the researchers ensured that all clinical and pathological processes were closely coordinated and supported by a highly developed infrastructure.
These data support the assumption that SARS-CoV-2 can use the olfactory mucosa as an entry point into the brain.
This is also supported by the close anatomical proximity of mucous membrane cells, blood vessels and nerve cells in the region.
In the olfactory lining, the virus appears to use neuroanatomical connections such as the olfactory nerve to reach the brain. However, it is important to emphasize that the COVID-19 patients involved in this study had what is known as a serious illness, which belongs to that small group of patients in whom the disease proves to be fatal. It is therefore not necessarily possible to apply the results of our study to cases with mild or moderate illnesses.
The way in which the virus clears away from the nerve cells has yet to be fully understood.
Our data suggests that the virus moves from nerve cell to nerve cell to reach the brain. However, it is likely that the virus is also transported through the blood vessels, as evidence of the virus has also been found in the walls of the blood vessels in the brain. “SARS-CoV-2 is nowhere near the only virus that can reach the brain via certain routes. Other examples include the herpes simplex virus and the rabies virus
Dr. Broken wheel
The researchers also looked at the way the immune system responds to infection with SARS-CoV-2. They not only found evidence of activated immune cells in the brain and in the olfactory mucosa, but also recognized the immune signatures of these cells in the cerebrospinal fluid. In some of the cases studied, the researchers also found tissue damage caused by stroke resulting from thromboembolism (that is, the blockage of a blood vessel by a blood clot).
In our eyes, the presence of SARS-CoV-2 in nerve cells of the olfactory mucosa provides a good explanation for the neurological symptoms in COVID-19 patients, such as: B. a loss of smell or taste. We also found SARS-CoV-2 in areas of the brain that control vital functions such as breathing. It cannot be ruled out that in patients with severe COVID-19, the presence of the virus in these areas of the brain may worsen respiratory function and worsen breathing problems due to SARS-CoV-2 infection of the lungs. Similar problems can arise with cardiovascular function.
Prof. Heppner. “”
* Meinhardt J et al., SARS-CoV-2 olfactory transmucosal invasion as a port of entry into the central nervous system in people with COVID-19. Nat Neurosci 2020. doi: 10.1038 / s41593-020-00758-5
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On this study
This study would not have been possible without the consent of the patients and / or their family members. The authors are very grateful to them. Post-mortem examinations performed by neuropathologists and pathologists on patients who have died of COVID-19 require the same personal protective equipment that those with e.g. B. HIV or tuberculosis is used. The results of this study were published on June 4, 2020 as a preprint (before the peer review). After completing the peer review process, the paper has now been published in Nature Neuroscience.