Evidence of SARS-CoV2 Entry Protein ACE2 in the Human Nose and Olfactory Bulb

Abstract

Usually, pandemic COVID-19 disease, caused by SARS-CoV2, presents with mild respiratory symptoms such as fever, cough, but frequently also with anosmia and neurological symptoms. Virus-cell fusion is mediated by angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) with their organ expression pattern determining viral tropism. Clinical presentation suggests rapid viral dissemination to the central nervous system leading frequently to severe symptoms including viral meningitis. Here, we provide a comprehensive expression landscape of ACE2 and TMPRSS2 proteins across human postmortem nasal and olfactory tissue. Sagittal sections through the human nose complemented with immunolabelling of respective cell types represent different anatomically defined regions including olfactory epithelium, respiratory epithelium of the nasal conchae and the paranasal sinuses along with the hardly accessible human olfactory bulb. ACE2 can be detected in the olfactory epithelium as well as in the respiratory epithelium of the nasal septum, the nasal conchae, and the paranasal sinuses. ACE2 is located in the sustentacular cells and in the glandular cells in the olfactory epithelium as well as in the basal cells, glandular cells, and epithelial cells of the respiratory epithelium. Intriguingly, ACE2 is not expressed in mature or immature olfactory receptor neurons and basal cells in the olfactory epithelium. Similarly, ACE2 is not localized in the olfactory receptor neurons albeit the olfactory bulb is positive. Vice versa, TMPRSS2 can also be detected in the sustentacular cells and the glandular cells of the olfactory epithelium. Our findings provide the basic anatomical evidence for the expression of ACE2 and TMPRSS2 in the human nose, olfactory epithelium, and olfactory bulb. Thus, they are substantial for future studies that aim to elucidate the symptom of SARS-CoV2 induced anosmia via the olfactory pathway.

Expression of the ACE2 virus entry protein in the nervus terminalis reveals the potential for an alternative route to brain infection in COVID-19

“…In humans, the number of nervus terminalis neurons is relatively small (a few hundred to a few thousand neurons depending on age, Brookover, 1917;Larsell, 1950;Jin et al, 2019). However, such a relatively small number may be sufficient to mediate viral infection, especially considering that the nervus terminalis directly innervates secretory cells of the Bowman's glands (Larsell, 1950) that are known to express ACE2 (Brann et al, 2020;Chen et al, 2020;Cooper et al, 2020;Ye et al, 2020;Zhang et al, 2020;Klingenstein et al, 2021) and readily become infected with SARS-CoV-2 (Ye et al, 2020;Leist et al, 2020;Meinhardt et al, 2020;Zhang et al, 2020;Zheng et al, 2020) (Fig. 4).…”

“…Cells expressing ACE2 are indicated in green, including sustentacular cells (SUS) and BG cells. Both of these cell types have been shown to express ACE2 (Bilinska et al, 2020;Brann et al, 2020;Chen et al, 2020;Ye et al, 2020;Zhang et al, 2020;Klingenstein et al, 2021). Cell types that have been documented to be infected by SARS-CoV-2 are indicated with pink asterisks.…”

The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models

“…To assess whether olfactory receptor neurons may be susceptible to infection by SARS-CoV-2, investigators have determined which cell types in the olfactory epithelium express the obligatory entry proteins for the new coronavirus, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2). These gene and protein expression studies were performed by RNAseq of identified cell types, or using markers for distinct cell types within the olfactory epithelium combined with gene or protein expression for ACE2 and TMPRSS2 [6,8,11,23,38,42,52,66,98,103,106]. The large majority of these studies concluded that sustentacular cells (the primary support cells in the olfactory epithelium) and cells in Bowman's glands express the virus entry proteins, while all human studies and the majority of animal studies reported that olfactory receptor neurons do not express ACE2, or express ACE2 only very rarely (Tables 1, 2 and 3).…”

Impact of COVID-19 Pandemic on Patients With Neurodegenerative Diseases

“…About 11% of those patients developed anosmia prior to any other clinical symptoms (Lechien et al, 2020). ACE2 has been found to be highly expressed in nasal goblet and ciliated cells, which strongly indicates the possibility that SARS-CoV-2 may enter the human brain through olfactory nerves (Klingenstein et al, 2021). Another potential invading route for SARS-CoV-2 is probably via ventricular choroid plexus into cerebrospinal fluid (CSF) and brain (Abate et al, 2020).…”