Photo: Michael Laue/RKI & Carsten Dittmayer/Charité

Charite.de

A research team from Charité - Universitätsmedizin Berlin used tissue samples from deceased COVID-19 patients to analyze how the novel coronavirus can penetrate the brain and how the immune system there reacts to the virus. The results now published in Nature Neuroscience * show that SARS-CoV-2 is transferred to the brain via the nerve cells of the olfactory mucosa. For the first time, the researchers succeeded in taking electron microscopic images of intact coronavirus particles in the olfactory mucosa.

That COVID-19 is not just a respiratory disease is now considered certain. Not only the lungs, the cardiovascular system, or the gastrointestinal tract, but also the central nervous system can affect SARS-CoV-2: More than a third of those affected by COVID-19 report neurological symptoms such as odor and Loss of taste, headache, fatigue, dizziness, and nausea. Occasional strokes and other serious illnesses also occur. Researchers have suspected the reason for this to be that the virus penetrates the brain and attacks certain cells there. But how does SARS-CoV-2 get there? Under the direction of Dr. Helena Radbruch from the Institute for Neuropathology at the Charité and Prof. Dr. Frank Heppner, director of the same institute, a multidisciplinary research team has now traced the entry of the virus into the nervous system and its further path in the brain.

For this purpose, experts from neuropathology, pathology, forensic medicine, virology, and clinical care examined the tissue samples from 33 people who had died at the Charité or Göttingen University Medical Center as a result of a COVID-19 infection - on average at an age of almost 72 years. Using state-of-the-art methods, the researchers analyzed samples from the olfactory mucosa and four different brain regions: They looked for the genetic material of SARS-CoV-2 both in the tissue network and in individual cells and a protein found in the virus envelope - the so-called spike protein. The team was able to detect the virus in various neuroanatomical structures that connect the eyes, mouth, and nose with the brain stem. The highest viral load was found in the olfactory mucosa. There, the research team was also able to make intact coronavirus particles visible for the first time with the help of special stains and electron microscope images: They were found both inside nerve cells and on the appendages of the cover cells located there. For these analyzes, excellent tissue quality was essential, which the research group achieved through close coordination between health care and pathological areas and a sophisticated infrastructure.

“On the basis of this data, we assume that SARS-CoV-2 can use the olfactory mucous membrane as an entry point into the brain, ”says Prof. Heppner. This is anatomically obvious: Here, mucous membrane cells, blood vessels, and nerve cells are very close together. "From the olfactory mucosa, the virus apparently uses neuroanatomical connections such as the olfactory nerve to reach the brain," adds the neuropathologist. “It is important to emphasize, however, that the people affected by COVID-19 by definition - they belong to the small group of patients who ultimately die from it - had shown a severe course. The results of our study can therefore not necessarily be transferred to mild or moderate cases. "

It has not yet been conclusively clarified how exactly the virus moves on from the nerve cells. "Our data suggest that the virus migrates from nerve cell to nerve cell in order to reach the brain," explains Dr. Broken wheel. "The virus is probably also transported via the blood vessel system at the same time, since virus could also be detected in the vascular walls in the brain." SARS-CoV-2 is not the only virus that can enter the brain via certain pathways. “Other examples of this are herpes simplex viruses and the rabies virus, which causes rabies,” explains the scientist.

The researchers also examined how the immune system reacts to the SARS-CoV-2 reacts: They detected activated immune cells in the brain and in the olfactory mucosa and discovered their immune signatures in the cerebral water. In some of the cases examined, they also found tissue damage from strokes that had arisen as a result of thromboembolism, i.e. blockage of the vessels by blood clots. "In our eyes, the SARS-CoV-2 infestation of the nerve cells in the olfactory mucosa provides a good explanation for the typical neurological symptoms of COVID-19 sufferers, such as odor and taste disorders," explains Prof. Heppner. “We also have SARS-CoV-2 found in regions of the brain that control vital functions such as breathing. It cannot be ruled out that in the case of severe COVID-19 courses, the virus infestation in these brain areas makes breathing more difficult - in addition to the impairment of respiratory function due to the virus infestation of the lungs. The same can apply to the heart and circulation. "