Study exposes human olfactory and brain cells as genuine viral targets of SARS-CoV-2

In a study published in the iScience journal, a research group from Switzerland shows that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptors and entry genes are expressed in the human olfactory neuroepithelial cells and brain by observing key molecular players implicated in the infectious process

The entry of SARS-CoV-2, which is a causative agent of coronavirus disease (COVID-19) pandemic, entails the use of spike glycoprotein to interact with the receptor angiotensin-converting enzyme-2 (ACE2). Attached to the cellular membrane is a serine protease TMPRSS2, which primes the spike glycoprotein and facilitates viral entry.

Consequently, the main targets of the virus – which are respiratory cells that line the respiratory airways – co-express both ACE2 and TMPRSS2. The nasal cavity also harbors respiratory cells, but there is an olfactory area responsible for regulating the sense of smell.

And indeed, the loss of smell is one of the symptoms of COVID-19; however, the notion that viruses may directly or indirectly affect the integrity and function of the sensory portion of the olfactory system is not entirely new. Some viruses actually disturb the neuroepithelium in manifold ways and often modify specific cell types, including neurons.

But whether the evident olfactory dysfunction linked to SARS-CoV-2 infection stems from a general inflammatory process in the nasal cavity or from a targeted perturbation of the olfactory neuroepithelium or olfactory bulb is still not clear.

In this new paper, the researchers from Switzerland (led by Dr. Leon Fodoulian from the University of Geneva) aimed to investigate the distribution of the SARS-CoV-2 receptor ACE2 in the human olfactory neuroepithelial cells, as well as in the brain.

A multidisciplinary methodological approach

This research endeavor was conducted by utilizing a multidisciplinary approach, which was based on their data and publicly available RNA-seq datasets, as well as on immunohistochemical stainings of mouse and human tissues.

More specifically, the researchers have collected biopsies using nasal endoscopic surgery from four adult patients and subsequently explored the potential expression of ACE2 and TMPRSS2. Immunohistochemistry was then used to evaluate the expression of ACE2 in the human nasal cavity.

In their study, transcriptomic analyses of whole tissue and single cells from human olfactory epithelia were pursued, and they have also explored two single-nucleus RNA-seq datasets in order to appraise ACE2 expression in the human brain precisely.

Sustentacular cells laden with receptors

The results have revealed a subset of olfactory sustentacular cells in the olfactory neuroepithelium (also known as the supporting cells implicated in odorant transformation and xenobiotic metabolism) express ACE2, but not olfactory sensory neurons.

"In the mouse, in which the olfactory mucosa is particularly well organized both in terms of pseudostratified layers and in terms of its very strict separation from the respiratory epithelium, we observed (similarly to humans) a clear expression of ACE2 in the apical border of sustentacular cells", explain study authors.

However, this distribution was not homogenous since ACE2 was observed in sustentacular cells that were extremely dorsally located but were completely absent from the more ventral zone of the olfactory neuroepithelium.

In any case, these cells were also found to co-express TMPRSS2, and the researchers have also unveiled ACE2 expression in a subset of cell types of the brain – including neuronal and non-neuronal cells.

A credible link with anosmia

In a nutshell, this study has shown that respiratory cells are not solitary players in the contact with the outside world that harbor molecular keys implicated in SARS-CoV-2 entry in the nose. Sustentacular cells, situated at the interface between the central nervous system and the olfactory cavity, share the same traits.

But how likely is it that such co-expression of ACE2 in olfactory sustentacular cells and their direct connection with the brain represents an underlying cause for SARS-CoV-2-induced anosmia?

"Taken together, and despite the fact that one cannot exclude inflammation and the infection of other non-neuronal cell types in the olfactory neuroepithelium as an origin of the SARS-CoV-2- induced anosmia, the link between the viral molecular entry tools expressed by olfactory sustentacular cells and the SARS-CoV-2-induced chemosensory alteration appears quite credible", conclude study authors.

In any case, the presence of various neuronal and non-neuronal cell populations that express ACE2 in the human brain is a research interest worth pursuing, with a vast possibility of practical applications down the line.

Journal reference:
Dr. Tomislav Meštrović

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university - University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.

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