key: cord-0694851-0m5gpexf
authors: Fodoulian, Leon; Tuberosa, Joel; Rossier, Daniel; Boillat, Madlaina; Kan, Chenda; Pauli, Véronique; Egervari, Kristof; Lobrinus, Johannes A.; Landis, Basile N.; Carleton, Alan; Rodriguez, Ivan
title: SARS-CoV-2 receptors and entry genes are expressed in the human olfactory neuroepithelium and brain
date: 2020-11-25
journal: iScience
DOI: 10.1016/j.isci.2020.101839
sha: 5886a512cda444c8229b068986076253366ed3f6
doc_id: 694851
cord_uid: 0m5gpexf

Reports indicate an association between COVID-19 and anosmia, as well as the presence of SARS-CoV-2 virions in the olfactory bulb. To test whether the olfactory neuroepithelium may represent a target of the virus, we generated RNA-seq libraries from human olfactory neuroepithelia, in which we found substantial expression of the genes coding for the virus receptor angiotensin-converting enzyme-2 (ACE2), and for the virus internalization enhancer TMPRSS2. We analyzed a human olfactory single-cell RNA-seq dataset and determined that sustentacular cells, which maintain the integrity of olfactory sensory neurons, express ACE2 and TMPRSS2. ACE2 protein was highly expressed in a subset of sustentacular cells in human and mouse olfactory tissues. Finally, we found ACE2 transcripts in specific brain cell types, both in mice and humans. Sustentacular cells thus represent a potential entry door for SARS-CoV-2 in a neuronal sensory system that is in direct connection with the brain.

TMPRSS2 ACE2

SARS-CoV-2 respiratory olfactory brain sensory neurons sustentacular cells 1 Introduction A novel virus from the Coronaviridae family, termed SARS-CoV-2, which emerged in December 2019 in East Asia, is currently expanding on the planet. Its exact history is unknown, but its genomic sequence suggests that it was transmitted from bats to humans via an intermediate animal host . It is now transmitted from human to human (Chan et al., 2020) , and from human to cat (Shi et al., 2020) .

Infection by SARS-CoV-2 is associated in our species with a severe respiratory syndrome called COVID-19, and is characterized by a substantial mortality rate Wang et al., 2020a; Zhou et al., 2020) .

Entry of SARS-CoV-2 into target cells depends on the Spike protein (S), which is present on the virus capsid (Letko et al., 2020; Walls et al., 2020) . Viral attachment involves an interaction between S and the angiotensin-converting enzyme-2 (ACE2), located on the surface of the target cell. One reported mechanism facilitating virus entry consists, in association with ACE2, in the priming of S by the cellular serine protease TMPRSS2, also attached to the cellular membrane, which eventually leads to the fusion between the cellular and the viral membranes (Hoffmann et al., 2020; Zhou et al., 2020) . Expectedly, the main targets of SARS-CoV-2, respiratory cells that line the respiratory airways, coexpress ACE2 and TMPRSS2 (Bertram et al., 2012) . Other proteins have been proposed to mediate SARS-CoV-2 internalization, in particular CD147 (Wang et al., 2020c) as an alternative receptor, and cathepsin (Ou et al., 2020) and furin-like proteases (Shang et al., 2020; Walls et al., 2020) as internalization activators.

Starting with anecdotal reports, both from SARS-CoV-2-infected patients and medical staff which suggested an association between viral infection and alterations of olfactory perception (Giacomelli et al., 2020; Mills, 2020; Perrigo, 2020) (and also taste sensitivity), the link between SARS-CoV-2 infection and olfactory dysfunction is today clearly established (Heidari et al., 2020; Hopkins et al., 2020; Luers et al., 2020; Moein et al., 2020; Spinato et al., 2020; Xydakis et al., 2020) . A smartphone app recording self-reported olfactory symptoms is even used to predict potential COVID-19 (Menni et al., 2020) . The olfactory perturbations, which range from mild to J o u r n a l P r e -p r o o f 4 more severe, are usually reversible, and affect up to 95% of COVID-19 patients depending on the report. Whether this olfactory perturbation results from a deterioration of the nasal sensor or of a more central perturbation is unclear, but the second hypothesis is not to be discarded since neurological manifestations of brain origin also appear to be associated with COVID-19 infection (Gutierrez-Ortiz et al., 2020; Moriguchi et al., 2020; Paterson et al., 2020; Poyiadji et al., 2020; Wang et al., 2020b) , and since SARS-CoV-2 virions have been found in the olfactory bulb (Nampoothiri et al., 2020) .

The mammalian nasal cavity can be divided into two areas: the respiratory and the olfactory areas, that are anatomically, cellularly and functionally different (Smith and Bhatnagar, 2019) ( Figure 1A ). In humans, the respiratory part covers the major part of the nasal cavity. It includes the turbinates and is lined with a ciliated pseudostratified columnar epithelium. Its function is to humidify, cool or warm the incoming air, and to trap small particles before they get into the lungs. The second nasal area corresponds to the olfactory neuroepithelium. In our species, it is located in the very dorsal part of the cavity. There, it contacts volatile chemicals entering the nose, an interaction which represents the first step in the process that leads to the identification of a given smell. This epithelium is pseudostratified, and includes

Bowman's glands, olfactory sensory neurons, sustentacular cells, microvillar cells, globose and horizontal basal cells (cells that keep dividing during adult life and replenish the pool of sensory neurons) (Moulton and Beidler, 1967) . Each sensory neuron extends a single axon towards the olfactory bulb, that crosses the cribriform plate before reaching the olfactory bulb in the brain. On its apical side, the olfactory neuron extends a dendrite, which ends in multiple and long specialized cilia in contact with the outside world. These are covered with odorant receptors and bath in the mucus that lines the nasal cavity. Olfactory sensory neuron dendrites are enwrapped inside specialized cells, termed sustentacular cells (Liang, 2018) , whose nuclei and cell bodies line the external layer of the thick neuroepithelium (although they remain attached to the basal lamina). The role played by the latter in maintaining the integrity and function of the neuroepithelium is critical, in a very similar way that Sertoli cells support germ cell development and survival. Indeed, contact of the olfactory mucosa with various drugs (such as 3-methylindole (Miller and O'Bryan, 2003) , the anti-thyroid drug methimazole (Bergstrom et al., 2003) , or J o u r n a l P r e -p r o o f 5 nickel sulfate (Jia et al., 2010) ) to which sustentacular cells are very sensitive, leads to transient anosmia.

Whether the apparent olfactory dysfunction associated with SARS-CoV-2 infection results from a general inflammation of the nasal cavity or from a more direct perturbation of the olfactory neuroepithelium or olfactory bulb is unclear (Cooper et al., 2020) . In any case, it is critical to determine whether this virus disposes of a niche to replicate just under the cribriform plate of the ethmoid bone, a structure with large holes through which olfactory neuron axonal projections directly contact the olfactory bulb, and offer a potential gateway to the brain. This latter, if expressing SARS-CoV2 receptors, could in turn become infected.

We asked whether specific cells present in the human olfactory neuroepithelium as well as cells in the brain may represent targets to SARS-CoV-2, by looking at the molecular players involved in infection, both at the RNA and protein levels.

J o u r n a l P r e -p r o o f 6

We collected biopsies via nasal endoscopic surgery from 4 adult patients, and explored the potential expression of ACE2 and TMPRSS2. Samples of both nasal respiratory and olfactory sensory epithelia were harvested. Bulk tissue RNA was extracted, libraries generated and sequenced ( Figure 1B ).

To assess the specificity of our dissection, we performed a differential expression analysis between the respiratory and olfactory epithelia datasets ( Figure 1B ). As expected, olfactory-specific genes, including olfactory receptor genes, CNGA2 and ANO2, OMP, and ERMN (encoding critical elements of the olfactory transduction cascade, a specific marker of mature olfactory sensory neurons and a marker of sustentacular cells, respectively), were significantly enriched in olfactory samples ( Figure 1C -1E). The presence of ACE2 and TMPRSS2 transcripts was then evaluated. We observed a mean of 7.1 and 63.7 TPMs in the respiratory epithelium samples for ACE2 and TMPRSS2 respectively ( Figure 1F ,1G), reflecting the presence of ciliated cells which represent targets of SARS-CoV-2. We found a mean of 4.6 and 76.1 TPMs in the sensory neuroepithelium samples for ACE2 and TMPRSS2 respectively ( Figure 1F ,1G), indicating the presence in this tissue of cells that may express both genes, or of a mix of cells that express either TMPRSS2 or

To identify putative viral targets transcribing both ACE2 and TMPRSS2 in the neuroepithelium, we took advantage of a very recently published dataset reported by Durante et al. (Durante et al., 2020) . This dataset contains the transcriptome of 28'726 single cells, collected during nasal endoscopic surgery of 4 adult patients.

Prior to any cell type analysis, we monitored the existence of cells that would transcribe both ACE2 and TMPRSS2 ( Respiratory cells are thus not the only cells in contact with the outside world that exhibit the molecular keys involved in SARS-CoV-2 entry in the nose. Sustentacular cells, which lay at the interface between the central nervous system and the olfactory cavity, share the same characteristics.

Quantification of gene transcripts at the single cell level, a commonly used proxy of protein abundance, often leads to very inaccurate predictions, up to a complete discordance between real transcript and protein levels (Bauernfeind and Babbitt, 2017; Liu et al., 2016) . Since it is the protein that matters here, and at the individual cell level, we investigated the expression of ACE2 and TMPRSS2 in tissues by immunohistochemistry. Given that ortholog tissue-specificity is highly conserved between tetrapod species (Kryuchkova-Mostacci and Robinson-Rechavi, 2016) , and in particular between mouse and humans (Liao and Zhang, 2006) , we analyzed mouse tissues in parallel to human ones.

J o u r n a l P r e -p r o o f 8 We first evaluated the potential ACE2 immunoreactivity of the mouse olfactory epithelium ( Figure 3A ,3B). To assess antibody specificity, we used independently three different anti-ACE2 antibodies, which were raised against the extracellular part (Ab1 and Ab3 developed in goat and rabbit respectively) or the intracellular part of ACE2 (Ab2, developed in rabbit). These antibodies were first evaluated to label colon and kidney tissues, which contain previously described ACE2-expressing cell types ( Figure S1A -S1J). In the olfactory cavity, a strong and defined labeling was observed in the respiratory epithelium in the nasal cavity and nasopharyngeal duct ( Figure We also evaluated TMPRSS2 immunoreactivity in the mouse olfactory epithelium ( Figure 3N ,3P). We tested two different antibodies, which were first evaluated on kidney tissue ( Figure S2 ). In the mouse main olfactory epithelium, sustentacular cells were positive for TMPRSS2, and several other cell types showed weak expression ( Figure 3N , Figure A similar somatic staining was also observed, with the same antibody, in proximal tubule cells of the mouse kidney ( Figure S1D ). Congruently with its pervasiveness in the single-cell transcriptomes, TMPRSS2 labeling was observed in many constituents of the nasal epithelium ( Figure 4H , Figure S4F ,S4G).

We sought to investigate whether the SARS-CoV-2 virus was present in sustentacular cells of patients infected with the virus. The olfactory sensory epithelium of two deceased SARS-CoV-2-infected individuals was analyzed. It was found to be highly damaged and largely detached from the basal lamina ( Figure 

which genome is closely related to the one of SARS-CoV-2 and whose effects on human tissues appear similar to those observed with SARS-CoV-2, has been observed in human brains (Ding et al., 2004; Gu et al., 2005; Xu et al., 2005) . Could SARS-CoV-2 replicate in the olfactory epithelium and could the infection spread to the brain? To explore the potential receptivity to SARS-CoV-2 infection of the various cell types in the brain, we evaluated, again, the potential coexpression of ACE2 and TMPRSS2 in neuronal and non-neuronal cell types in the central nervous system of both mice and humans.

For the mouse, we took advantage of two available single-cell RNA-seq datasets (Saunders et al., 2018; Zeisel et al., 2018) , consisting in two broad collections of mouse brain cell types. In the first collection, published by Zeisel et al. (Zeisel et al., 2018) , that include non-neuronal cells, we found a very limited number of cell types that express Ace2 ( Figure 5A ). These cells are related to pericytes and coexpress the mural cell marker Rgs5. They express Ace2 transcripts, as well as Rgs5, a pericyte marker ( Figure 5B ). Tmprss2, whose transcripts were barely detected, was J o u r n a l P r e -p r o o f expressed by even fewer cell types ( Figure 5A ), with Purkinje cells displaying the highest expression level. These observations were confirmed by the second mouse dataset (Saunders et al., 2018) , in which mural cells were the main cell type that expressed Ace2 ( Figure 5C ). None of these cell populations coexpressed Tmprss2.

Although showing substantial expression of ACE2 in the mouse brain, our data did not replicate the widespread expression of ACE2 in the central nervous system previously reported by others, which found ACE2 in the motor cortex, raphe, and in nuclei involved in the regulation of cardiovascular function (Doobay et al., 2007) . To precisely evaluate the expression of ACE2 in the mouse brain, and in particular at investigating the distribution of the SARS-CoV-2 receptor ACE-2 in the human olfactory neuroepithelium and in the brain. Other groups, whose results are mostly in line with our findings, have also addressed parallel questions (Bilinska et al., 2020; Brann et al., 2020a; Brann et al., 2020b; Sungnak et al., 2020) .

Taking a multidisciplinary approach, based both on our own and publicly available RNA-seq datasets, and on immunohistochemical stainings of mouse and human tissues, we demonstrate here that a subset of olfactory sustentacular cells in the olfactory neuroepithelium, but not olfactory sensory neurons, expresses ACE2, the main player in the binding and entry of the SARS-CoV-2 into human cells. These cells were found to coexpress TMPRSS2, a serine protease known to facilitate viral entry. We also found ACE2 expression in specific cell types of the brain, including neuronal and non-neuronal cell types.

We first determined, using transcriptomic analyses of whole tissue and single cells from human olfactory epithelia, that a subset of sustentacular cells expresses ACE2.

We recently reported this finding as a preprint on BioRxiv (Fodoulian et al., 2020) , which is in agreement with another preprint on the same server (Brann et al., 2020a) .

We then confirmed this finding in mouse and human tissues by immunohistochemistry. 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 (in agreement with a very recent report citing our BioRxiv article (Bilinska et al., 2020) ). This distribution was however non-homogenous, since ACE2 was present in the most dorsallylocated sustentacular cells, but was entirely absent from more ventrally-located ones. Such dichotomy between the dorsal and the ventral neuroepithelium is reminiscent, in the mouse, of the dorsally-located olfactory neurons, which are known to share molecular markers that are dissimilar from those present in more ventral neurons (Gussing and Bohm, 2004) . This known contrast is not limited to the 12 neuronal identities, since the function and response to stress of these dorsallylocated neurons also appears to be different (Kobayakawa et al., 2007; Tuerdi et al., 2018) . We now add a non-neuronal cell type to this dorsoventral neural dichotomy.

In the human olfactory neuroepithelium, a similar labeling of ACE2 was observed in sustentacular cells, although the staining was mainly present in the somata. Again, as observed in the mouse, some of these cells were positive and others were negative for ACE2. These human ACE2-expressing sustentacular cells were found isolated or in small clusters, intermingled with sustentacular cells negative for ACE2, or even sometimes intermingled with respiratory epithelium, an expected observation given the relatively poor organization of the human olfactory neuroepithelium, in particular in aged individuals.

How likely is it that the coexpression of ACE2 in olfactory sustentacular cells is 

ability. Indeed, in addition to anosmia, ageusia has also been reported (Cooper et al., 2020; Giacomelli et al., 2020) . Whether these reports truly reflect taste anomalies or rather olfactory perturbations that may drastically affect the flavor of food, is unclear. However, this potential double effect on two chemosensory systems that share nothing at the periphery may suggest a more central alteration, involving for example a direct infection of the brain by SARS-CoV-2. But this would require potential targets. We identified various cell types in the brain that express ACE2, although at relatively low levels in humans. In the mouse, we detected ACE2 expression in brain vascular endothelial cells and pericytes, but not in neurons. In humans, we found ACE2 transcripts in non-neuronal cell types such as astrocytes and microglia, but also in neurons, in particular Purkinje and cortical layer 5 neurons.

Whether these different cell types reflect differences in tissue specificity between the two mammalian species is unclear, since RNA-seq discordances may results from differences in the sequencing depth, sequencing protocols (single-nucleus versus single-cell RNA-seq), dissimilar mRNA half-lives, or variable cell type selection strategies between the different studies. But whatever the reason for the discordances, these data point to potential targets for SARS-CoV-2 infection in brain cells.

Similar to the infection of the olfactory neuroepithelium by SARS-CoV-2, the transport of viral particles from the olfactory mucosa to the brain would not be a first.

In 1935 already, the olfactory route was hypothesized (because of its direct connection with the brain), to represent a portal for entry of viruses into the central nervous system (Flexner, 1936) . We know today that the olfactory nerve route is indeed used by various viruses to reach the brain, including HSV1, poliovirus, MHV (a coronavirus), paramyxoviruses, Hendra virus, Nipah virus, influenza virus, adenoviruses, bunyaviruses, VSV, and many others (Durrant et al., 2016) .

Although most pathogenic microorganisms appear to access the CNS via the axons of olfactory sensory neurons, other routes of entry through the cribriform plate have been described. For instance, the amoeba Naegleria fowleri penetrates the olfactory epithelium either via sustentacular cells, or in a paracellular way, and then travels along the nerve bundle through the cribriform plate (Jarolim et al., 2000) . Moreover, the bacterium Burkholderia pseudomallei causes a widespread loss of OSNs, which leads to the degeneration of the olfactory nerves (St John et al., 2014) . B.

pseudomallei then migrates along the empty conduits of olfactory nerves towards the CNS. An even more convincing example may be the neurotropic MHV virus, which is found in high concentrations within the perineurium of the olfactory nerve and in the brain after nasal infection (Barthold, 1988 ) (olfactory sensory neurons lack the main MHV virus receptor CEACAM1 (Brann et al., 2020b; Miura et al., 2008) ).

SARS-CoV-2 virions have in fact been observed in the human olfactory bulb (Nampoothiri et al., 2020) . SARS-CoV particles have also been found in the human brain (Ding et al., 2004; Gu et al., 2005; Xu et al., 2005) . Adding to these observations, brain lesions were observed in a transgenic mouse model expressing the human ACE2 in the nose and infected intranasally with SARS-CoV (Netland et al., 2008) . Moreover, a retrospective case study on 214 COVID-19 patients reported neurological manifestations possibly correlated with the severity of the disease (Mao et al., 2020) (with the confounding factor that old people are more likely to develop severe disease). As worrying are suggestions that a subset of patients infected with the virus but lacking respiratory symptoms may exhibit neurologic symptoms (Wang et al., 2020b) , and that they may be associated with encelphalitis ( cranialis (Gutierrez-Ortiz et al., 2020) . Given, as we showed here, the presence in the human brain of various neuronal and non-neuronal cell populations expressing ACE2, this certainly appears to be a line of investigation worth pursuing.

We investigated whether the SARS-CoV-2 virus was present in sustentacular cells of patients infected with the virus. We analyzed the olfactory sensory epithelium of two deceased SARS-CoV-2-infected individuals. However, the epithelium was found to be highly damaged and largely detached from the basal lamina, hindering the potential identification of viral particles in sustentacular cells. Hence, we could not determine whether the SARS-CoV-2 virus is indeed present in sustentacular cells of infected patients. Whether the histological damage was caused by the virus cannot be determined based on the few samples analyzed.

Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Ivan Rodriguez (ivan.rodriguez@unige.ch).

This study did not generate new unique reagents.

All datasets generated during and/or analyzed during the current study have been 

The authors declare no competing interests. Olfactory and respiratory epithelium sample data points are shown on a white and grey background respectively. OE: olfactory epithelium, RE: respiratory epithelium. 

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