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The researchers found how SARS-CoV-2 reached the brains of patients with COVID-19

Ciliated cell in the olfactory mucosa with SARS-CoV-2

An electron microscope image (ultra-thin area, artificially stained) shows an area of ​​the ciliary cell in the olfactory mucosa. A large number of intact SARS-CoV-2 particles (red) are found both in the cell and in cellular processes. Yellow: kinocilia. Credit: Michael Laue / RKI & Carsten Dittmayer / Charité

Using tissue samples after death, a team of researchers from CharityUniversity Medicine in Berlin have studied the mechanisms by which the new coronavirus can reach the brains of patients with COVID-19and how the immune system reacts to the virus after it does. The results show this SARS-CoV-2 Enters the brain through nerve cells in the olfactory mucosa, are published in Natural neurology. For the first time, researchers have been able to create electron microscopic images of intact coronavirus particles in the olfactory mucosa.

It is now recognized that COVID-19 it is not a pure respiratory disease. In addition to affecting the lungs, SARS-CoV-2 may affect the cardiovascular system, gastrointestinal tract and central nervous system. More than one in three people with COVID-19 report neurological symptoms such as loss or change in smell or taste, headache, fatigue, dizziness and nausea. In some patients, the disease can even lead to stroke or other serious conditions. Until now, researchers suspected that these manifestations must be caused by a virus that enters and infects certain cells in the brain. But how does it happen SARS-CoV-2 do i get there Under the joint guidance of Dr. Helena Radbruch from CharityThe Department of Neuropathology and the director of the department, Prof. Dr. Frank Hepner, a multidisciplinary team of researchers have already monitored how the virus enters the central nervous system and then invades the brain.

Nerve cell inside the olfactory mucosa infected with SARS-CoV-2

Immunofluorescence staining showed a nerve cell (pink) inside the olfactory mucosa that was infected with SARS-CoV-2 (yellow). The supporting (epithelial) cells appear blue. Credit: Jonas Franz / Universitätsmedizin Göttingen

As part of this study, experts in neuropathology, pathology, forensics, virology and clinical care examined tissue samples from 33 patients (mean age 72) who died in both Charity or the University Medical Center of Göttingen after the conclusion of a contract COVID-19. Using the latest technology, the researchers analyzed samples taken from the olfactory mucosa of the dead patients and from four different brain areas. Both tissue samples and individual cells were tested SARS-CoV-2 genetic material and a ‘spike protein’ 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 revealed the highest viral load. Using special tissue spots, the researchers were able to create the first-of-its-kind images with electron microscopy of intact coronavirus particles in the olfactory mucosa. They are found both in nerve cells and in processes extending from nearby supporting (epithelial) cells. All samples used in this type of image-based analysis must be of the highest possible quality. To ensure that this is the case, the researchers made sure that all clinical and pathological processes are closely linked and maintained by a complex infrastructure.

“These data support the idea that SARS-CoV-2 is able to use the olfactory mucosa as an entrance for the brain, “says Prof. Hepner. This is also supported by the close anatomical proximity of the mucosal cells, blood vessels and nerve cells in the area. “Once in the olfactory mucosa, the virus appears to use neuroanatomical connections, such as the olfactory nerve, to reach the brain,” the neurologist added. “It is important to emphasize, however COVID-19 the patients in this study had what could be defined as a severe illness belonging to that small group of patients in whom the disease turned out to be fatal. Therefore, the results of our study do not necessarily apply to cases of mild or moderate disease. “

The way in which the virus passes from nerve cells remains to be fully understood. “Our data show that the virus moves from nerve cell to nerve cell to reach the brain,” explains Dr. Radbruch. She added: “However, the virus is also likely to be transported through blood vessels, as evidence of the virus has also been found in the walls of blood vessels in the brain.” SARS-CoV-2 it is far from the only virus capable of reaching the brain in certain ways. “Other examples include the herpes simplex virus and the rabies virus,” explains Dr. Radbruch.

Researchers have also studied how the immune system responds to infection with SARS-CoV-2. In addition to finding evidence of activated immune cells in the brain and olfactory mucosa, they found immune signatures of these cells in the brain fluid. In some of the cases studied, the researchers also found tissue damage caused by a stroke as a result of thromboembolism (ie blockage of a blood vessel by a blood clot). “In our eyes, the presence of SARS-CoV-2 in the nerve cells of the olfactory mucosa gives a good explanation for the neurological symptoms found in COVID-19 patients, such as loss of sense of smell or taste, ”explains Prof. Hepner. “It simply came to our notice then SARS-CoV-2 in areas of the brain that control vital functions such as respiration. This cannot be ruled out in patients with severe form COVID-19, the presence of the virus in these areas of the brain will have an exacerbating effect on respiratory function, adding to breathing problems due to SARS-CoV-2 lung infection. Such problems can occur in connection with cardiovascular function. “

Reference: “Olfactory transmucosal invasion of SARS-CoV-2 as a port for entry into the central nervous system in persons with COVID-19” by Jenny Meinhard, Josefin Radke, Carsten Dietmeier, Jonas Franz, Carolina Thomas, Ronja Motes, Michael Laue, Julia Schneider, Sebastian Brunkin, Selina Grewell, Malte Lehmann, Olga Hassan, Tom Ashman, Eliza Schumann, Robert Lorenz Chua, Christian Conrad, Roland Ayles, Werner Stenzel, Mark Windgassen, Larissa Rössler, Hans-Hilmer Hunslom Goebel Martin, Andreas Nitsche, Walter J. Schulz-Schaeffer, Samy Hakroush, Martin S. Winkler, Björn Tampe, Franziska Scheibe, Péter Körtvélyessy, Dirk Reinhold, Britta Siegmund, Anja A. Kühl, Sefer Elezkurtaj, David Horbars L, -Hepner, Christine Stadelman, Christian Drosten, Victor Max Corman, Helena Radbruch and Frank L. Hepner, November 30, 2020, Natural neurology.
DOI: 10.1038 / s41593-020-00758-5

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