In a study published in iScience Jurnal, a research group from Switzerland showed that the receptor and entry gene for coronavirus 2 (SARS-CoV-2) severe acute respiratory syndrome is expressed in human olfactory nerve cells and the brain by observing key molecular players involved in the infection process.
The entry of SARS-CoV-2 which is the causative agent for the coronavirus disease pandemic (COVID-19) requires the use of a spike. glycoproteins to interact with the angiotensin-converting enzyme-2 (ACE2) receptor. Attached to the cell membrane are serine proteases TMPRSS2, which prioritizes glycoprotein spikes and facilitates viral entry.
As a result, the main target of the virus – namely the respiratory cells lining the respiratory tract – together express ACE2 and TMPRSS2. The nasal cavity also houses respiratory cells, but there is an area of smell which is responsible for regulating the sense of smell.
And indeed, loss of smell is one of the causes symptoms of COVID-19; However, the notion that viruses can directly or indirectly affect the integrity and functioning of the sensory parts of the olfactory system is not new. Some viruses actually interfere with the neuroepithelium in various ways and often modify certain types of cells, including neurons.
But whether the olfactory dysfunction shown to be associated with SARS-CoV-2 infection originates from a generalized inflammatory process in the nasal cavity or from a targeted disorder of the olfactory neuroepithelium or olfactory bulb is unclear.
In this new paper, researchers from Switzerland (led by Dr. Leon Fodoulian of the University of Geneva) aim to investigate the distribution of the SARS-CoV-2 ACE2 receptor in human olfactory neuroepithelial cells, as well as in the brain.
Multidisciplinary methodological approach
This research effort was carried out using a multidisciplinary approach, based on its data and publicly available RNA-seq datasets, as well as immunohistochemical staining of mice and human tissue.
More specifically, the investigators have collected biopsies using endoscopic nasal surgery from four adult patients and then explored the potential for expression of ACE2 and TMPRSS2. Immunohistochemistry was then used to evaluate ACE2 expression in the human nasal cavity.
In their study, transcriptomic analysis of entire tissues and single cells of the human olfactory epithelium was pursued, and they have also explored two single-core RNA-seq data sets to assess ACE2 expression in the human brain precisely.
Sustentacular cells loaded with receptors
The results have revealed that a subset of olfactory support cells in the olfactory neuroepithelium (also known as support cells involved in odor transformation and xenobiotic metabolism) express ACE2, but not olfactory sensory neurons.
“In mice, where the olfactory mucosa is well structured both in terms of the pseudo layer and in terms of its very tight separation from the respiratory epithelium, we observed (similar to humans) clear ACE2 expression at the apical boundaries of the support cells”, explain the study authors.
However, this distribution is not homogeneous because ACE2 is observed in cells that are located very dorsally but completely absent in the more ventral zone of the olfactory neuroepithelium.
However, these cells were also found to express TMPRSS2, and the researchers also revealed ACE2 expression in a subset of brain cell types – including nerve cells and non-neurons.
Credible link with anosmia
In short, this study has shown that respiratory cells are not the only players in contact with the outside world which stores the molecular keys involved in the entry of SARS-CoV-2 in the nose. Sustentacular cells, located at the interface between the central nervous system and the olfactory cavity, have the same properties.
But what is the likelihood that the co-expression of ACE2 in olfactory-supporting cells and its direct connection to the brain is the underlying cause of SARS-CoV-2-induced anosmia?
“Taken together, and despite the fact that one cannot exclude inflammation and infection of other types of non-neuronal cells in the olfactory neuroepithelium as the origin of SARS-CoV-2- induced anosmia, the relationship between the means of entry of viral molecules is revealed by the olfactory support and SARS-CoV-2-induced chemosensory changes appear to be quite credible “, the study authors concluded.
However, the existence of a wide variety of neuronal and non-neuronal cell populations that express ACE2 in the human brain is a research interest that needs to be pursued, with possible practical applications in the future.