In COVID-19, the Nose Gets Infected, and The Nerves Get Damaged: Two New Studies [COVID-19 Updates]

Two new studies published today as preprints suggest that SARS-CoV-2, the coronavirus that causes COVID-19, infects the nose and causes anosmia, the loss of a sense of smell, by damaging the nerves.

Preprints are papers that are destined for peer-reviewed journals but have not yet been peer reviewed. The vast majority of reliable information circulating about COVID-19 is coming from preprints.

The first paper used isolated human airway epithelia. Epithelia are the layers of cells that line the surfaces of all our organs. In this case, the airway epithelia included layers from the bronchus (the airway that branches off from the windpipe to feed the lungs) and from the nose.

The researchers isolated SARS-CoV-2 from a nasal swab and used it to infect the airway epithelia. The infection developed faster in the bronchial cells than in the nasal cells, and reached a higher peak in the bronchial cells, but the infection nevertheless rapidly infected both types of cells.

I predicted SARS-CoV-2 would infect the nose yesterday. I predicted this on the basis of two main pieces of evidence. First, the paper showing it infected the throat used oropharyngeal swabs and nasopharyngeal swabs. Oropharyngeal swabs reach the throat through the mouth and nasopharyngeal swabs reach the throat through the nose. There was no difference in viral load between the two swabs. So, either it's all coming from the throat, which was emphasized in the paper, or it's equally coming from the nose and mouth in addition to the throat.

The second point is that ACE2 expression is the primary determinant of whether a cell can be infected. A 2004 paper showed that the epithelia of the nose, mouth, and throat do express ACE2, but they do so under the surface, on the basolateral side of the cell that is hidden from the environment, rather than on the apical surface, which faces the environment. They suggested that SARS-CoV, the closely related predecessor of SARS-CoV-2, would not be able to infect these tissues since the virus would not have access to the underside of the cell while entering the nose and mouth from the environment. However, if the throat can be infected, that probably means that the viruses easily slip between the cells to gain access to the ACE2 on their undersides, in which case they should do so just as easily in the nose and mouth.

This underscores my suggestion yesterday to use a copper-based nasal spray for prevention before and after potential exposure events. (Unfortunately, the spray I suggested sold out on Amazon yesterday; I will contact the company and see if I can get them to ramp up their Amazon supply).

In this study, the virus primarily replicated in goblet cells, which produce mucous, and ciliated cells, which use hairlike projections called “cilia” to move mucous and debris. This is highly consistent with the study I wrote about Wednesday morning, showing that, in the lung, ACE2 is mostly expressed in ciliated cells and goblet cells, and that smoking strongly increases the amount of ACE2 expressed in the lung by dramatically increasing the number of mucous-producing goblet cells.

While the first paper dealt with the respiratory cells of the nose, the cells that contribute to our ability to breath and to filter, warm, and moisten the air we breath, the second study dealt with cells involved in our ability to smell. Patients and medical personnel are widely reporting that COVID-19 frequently causes reversible anosmia, a temporary loss of smell. Could this be from the virus causing nerve damage?

The nose is full of sensory neurons, which carry information from odor-carrying chemicals (odorants) to the brain, where our brain synthesizes the information to create the perception of smell. Each neuron has long branches called dendrites that are responsible for collecting the information carried by odorants. The dendrites have long cilia (again, the hair-like projections) that project into the mucous of the nasal passages with odorant receptors. The dendrites are each wrapped in supportive cells known as sustentacular cells. The sustentacular cells create the thick outer layer of what known as the neuroepithelium, the whole complex of cells needed to sense smells, and they are in direct contact with the outer environment.

If the sustentacular cells die, the whole neuroepithelium degenerates, and this is often the cause of anosmia.

The researchers didn't study live infections, but they assessed the vulnerability of the cells to SARS-CoV-2 infection by looking for two proteins. The first is ACE2, the protein that the virus first binds to with its own “spike” protein in order to attach to the cell. The second is an enzyme known as “transmembrane protease, serine 2” and abbreviated TMPRSS2. This enzyme processes the viral spike protein in a way that enables the virus to fuse with the cell membrane. Both of these events are required for the virus to enter the cell.

They reasoned that any cells expressing both ACE2 and TMPRSS2 in the cell membrane will be vulnerable to infection.

Olfactory neurons had little or no expression of either protein.

A variety of other cells expressed low levels of the two proteins.

The sustentacular cells, however, expressed high levels of both proteins. In fact, they expressed the two proteins at levels that are similar to those expressed in respiratory ciliated cells. This suggests that the sustentacular cells are just as likely to be infected as the ciliated cells and goblet cells of the airway, whose vulnerability to infection was shown directly in the first study.

Altogether, these two brand new papers, hot off the press, suggest that the virus is likely to be directly infecting the nose, focused on the mucous-producing cells and ciliated cells of the airway, and the sustentacular cells of the epithelium.

The direct attack on the sustentacular cells is probably what is causing the widely reported reversible loss of the sense of smell.

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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.


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