Coronavirus: infection in the nose cleared up – SARS-CoV-2 apparently does not affect the olfactory cells themselves, but their supporting cells –

Contrary to what we thought: The olfactory cells in our nose are apparently not the primary gateway for SARS-CoV-2, as a study has now revealed. Instead, the coronavirus seems to attack the supporting cells of the nasal mucosa – auxiliary cells that supply the olfactory neurons with nutrients. Their failure could be the indirect reason for the frequent loss of smell with Covid-19. At the same time, this could mean that SARS-CoV-2 cannot attack our nerve cells directly – that would be good news.

The nose has long been considered the first target of the coronavirus SARS-CoV-2. Studies show that the ciliary cells of the nasal mucous membrane, which are covered with cilia, have a particularly large number of ACE2 receptors on their surface and are therefore susceptible to infection with the virus. At the same time, the loss of smell and taste typical of Covid-19 suggested that the olfactory cells located in the mucous membrane are also attacked by SARS-CoV-2 – even if they hardly carry ACE2. A possible indication of this was the detection of virus particles in the olfactory mucosa and on the olfactory bulb.

Structure of the olfactory mucosa © ttsz/ Getty images

In search of the olfactory epithelium

The problem, however, is that it is extremely difficult to sample human olfactory cells. Because the olfactory mucous membrane sits deep in the back of the nose and also does not form a coherent epithelium. “Put simply, it is almost impossible to obtain samples of pure olfactory mucosa from a person,” explain Mona Khan from the Max Planck Research Center for Neurogenetics in Frankfurt and her colleagues. Such a biopsy is not reasonable in living patients.

The few samples analyzed so far therefore came from autopsies of deceased Covid 19 patients, but were often only removed from stretcher after death due to the risk of infection. The informative value was therefore rather low. That is why Khan and her team have developed a new protocol to be able to take tissue samples from the nasal mucous membranes and the olfactory bulb within the first hour and a half after the death of a patient.

Using special staining methods and an antibody-based analysis method called RNAscope, the team was then able to stain the different cell types of the nasal mucosa and examine them for RNA of the coronavirus SARS-CoV-2.

No viruses in the olfactory cells

The result: no traces of viral RNA could be seen in the olfactory cells. “We could not find any evidence of an infection of the olfactory cells,” write Khan and her colleagues. The cells of the olfactory bulb were also found to be virus-free. The gene activity of the olfactory receptors in the olfactory cells was also not changed by the infection with SARS-CoV-2 in the patients, as additional analyzes showed.

But there is another cell type in the olfactory epithelium that seems to be all the more susceptible to the coronavirus: “Our results show that SARS-CoV-2 infects the supporting cells in the olfactory epithelium of Covid-19 patients and multiplies strongly in these cells” , reports Khan’s colleague Peter Mombaerts. These cells around the olfactory cells have so far been little researched, but are considered auxiliary cells that supply the sensory cells with metabolic products, among other things.

Indirect damage through infestation of the auxiliary cells

According to the research team, these results suggest that the coronavirus is not a neurotropic virus – contrary to previous assumptions, it may not be able to directly infect nerve cells. In addition, nerve cells usually have neither ACE2 nor TMPRSS2 on their surface – they therefore lack the docking points for the virus. In addition, a replication of the coronavirus in the olfactory sense cells has never been detected in Covid. 19 patients, as Khan and her colleagues explain.

Instead, SARS-CoV-2 seems to damage the nerves and the brain of affected patients primarily indirectly – among other things by attacking the auxiliary cells that are important for the function of the neurons. If these supporting cells then fail, this impairs the function of the olfactory sense cells and this in turn could explain why an infection so often leads to disorders of the olfactory sense.

Contradictory to studies with brain cells

However: The current results suggest that SARS-CoV-2 does not affect the nervous system per se. At least neurons without ACE2 receptors seem to be largely protected. The situation is different in the brain and some other parts of the nervous system, in which neurons certainly have ACE2 receptors. In a study on brain organoids, researchers have already directly observed how SARS-CoV-2 penetrates brain cells and multiplies in them.

Khan and her team admit that their study does not allow a general statement. “Admittedly, the lack of evidence in this case does not yet mean evidence of a lack,” they state. They do not rule out that the coronavirus may attack the olfactory neurons in some patients and courses. In addition, their results initially only apply to the sensory cells of the olfactory system.

The study underlines once again that the behavior of the coronavirus and the course of an infection are far from being fully understood. The interactions between virus, nervous system and immune system in particular are still largely in the dark – a lot of further research will be necessary here. (Cell, 2021; doi: 10.1016/j.cell.2021.10.027)

Source: Max Planck Society

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