A research team from Charité – Universitätsmedizin Berlin has used tissue samples from deceased COVID-19 patients to analyse how the novel corona virus can penetrate the brain and how the immune system reacts to the virus there. The results now published in Nature Neuroscience* show that SARS-CoV-2 enters the brain via the nerve cells of the olfactory mucosa. For the first time, the researchers have succeeded in producing electron microscopic images of intact corona virus particles in the olfactory mucosa.
The fact that COVID-19 is not only a respiratory disease is now considered certain. SARS-CoV-2 can affect not only the lungs, the cardiovascular system or the gastrointestinal tract, but also the central nervous system: More than one third of COVID-19 patients report neurological symptoms such as loss of smell and taste, headaches, fatigue, dizziness and nausea. Occasionally there are also strokes and other serious diseases. Researchers have suspected that this is caused by the virus entering the brain and attacking certain cells there. But how does SARS-CoV-2 get there? A multidisciplinary research team led by Dr Helena Radbruch of the Institute of Neuropathology at the Charité and Prof. Dr Frank Heppner, Director of the same institute, has now traced the virus‘ entry into the nervous system and its further path in the brain.
To this end, experts from neuropathology, pathology, forensic medicine, virology and clinical care examined the tissue samples of 33 people who had died at the Charité or Göttingen University Hospital as a result of COVID-19 infection – on average at an age of just under 72 years. Using state-of-the-art methods, the researchers analysed samples from the olfactory mucosa and four different brain regions: They searched for the genetic material of SARS-CoV-2 and a protein of the virus envelope – the so-called spike protein – both in the tissue network and in individual cells. The team thus succeeded in identifying the virus in various neuroanatomical structures that connect the eye, 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 visualise intact corona virus particles for the first time with the help of special staining and electron microscopic images: they were found both inside nerve cells and on the extensions of the cover cells located there. An excellent tissue quality was elementary for these analyses, which the research group achieved through close coordination between disease-causing and pathological areas and a sophisticated infrastructure.
„On the basis of these data, we assume that SARS-CoV-2 can use the olfactory mucosa as an entry portal into the brain,“ says Prof. Heppner. This is also anatomically obvious: here, mucosal 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. „However, it is important to emphasise that the COVID-19 patients we examined had, by definition – they belong to the small group of patients who ultimately die from it – a severe course. The results of our study cannot therefore necessarily be transferred to mild or moderate cases.
It is not yet clear how exactly the virus moves from the nerve cells. „Our data suggest that the virus travels from nerve cell to nerve cell to reach the brain,“ explains Dr Radbruch. „However, it is likely that the virus is also transported via the blood vessel system at the same time, as virus could also be detected in the vessel walls in the brain“. SARS-CoV-2 is not the only virus that can reach the brain via certain pathways. „Other examples are herpes simplex viruses and the Rabies virus, which causes rabies,“ she said.
The researchers also investigated how the immune system reacts to SARS-CoV-2 infection: they detected activated immune cells in the brain and olfactory mucosa and discovered their immune signatures in the cerebral fluid. In some of the cases studied, they also found tissue damage caused by strokes as a result of thrombembolic events, i.e. blockages in blood vessels caused 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 olfactory and taste disorders,“ explains Prof. Heppner. „We have also found SARS-CoV-2 in brain regions that control vital functions such as breathing. It cannot be ruled out that in severe COVID-19 cases, the virus infestation in these brain areas may make breathing more difficult – in addition to the impairment of respiratory function by the virus infestation of the lungs. The same may apply to the heart and circulation“.
*Meinhardt J et al, Olfactory transmucosal SARS-CoV-2 invasion as port of central nervous system entry in individuals with COVID-19 Nat Neurosci 2020. doi: 10.1038/s41593-020-00758-5
About the study
A prerequisite for the study was the consent of the patients or their relatives, for which the research group explicitly thanked them. In the case of COVID-19 deceased, neuropathologists and pathologists perform an autopsy in protective equipment as would be used for deceased people with tuberculosis or HIV infection. The study results were published as a preprint on 4 June 2020. After completion of the peer review process, the work has now been published in the journal Nature Neuroscience.