Severe acute respiratory syndrome (SARS)-Coronavirus 2 (SARS-CoV-2) has recently been identified as the causative agent of a new severe respiratory disorder, known as coronavirus 19 disease (COVID-19), which was first detected in Wuhan, China, in December 2019 (Zhu et al., 2020). SARS-CoV-2 belongs to the Coronaviridae family, which includes evolutionary related enveloped (+) strand RNA viruses of vertebrates, such as seasonal common coronaviruses, SARS-CoV and Middle East Respiratory Syndrome (MERS)-CoV, which are responsible for severe clinical syndromes (Lu et al., 2020).

SARS-CoV-2 is highly transmissible (Sanche et al., 2020; Zheng, 2020). By the end of September 2020, SARS-CoV-2 had already infected more than 34 million people worldwide (Worldometers.info, 2020). Transmission occurs primarily through inhalation of droplets emitted from an infected person or through contact with contaminated surfaces on which viruses can remain infectious for several days (van Doremalen et al., 2020). The difficulty in controlling the spread of SARS-CoV-2 is in part due to the unusual shedding of the virus by asymptomatic individuals (Gandhi et al., 2020). While most infected people only experience mild to moderate respiratory symptoms after an incubation period of up to 14 days, others face severe symptoms ultimately leading to acute respiratory distress syndrome (ARDS) associated with a cytokine storm syndrome (CSS) (Wadman and Kaiser, 2020). The pulmonary pathobiology of COVID-19 differs from other severe respiratory infections with typical ground glass opacities and vascular endotheliitis and angiogenesis (Ackermann et al., 2020). Although COVID-19 is a disease initiated in the lungs, it is clear that the symptoms affect other organs and that the most severe cases present multisystem involvement (Wadman and Kaiser, 2020; Varga et al., 2020). Understanding of these disorders outside the lungs is still limited, but probably essential to suggest appropriate treatment strategies. Over 1, 000,000 individuals have died from COVID-19 at the end of September 2020 (Worldometers.info, 2020).

SARS-CoV-2 is closely related to SARS-CoV, which was responsible for a global outbreak in 2003. The high similarities seen in the spike (S) glycoproteins exposed on the surface of virions quickly suggested that SARS-CoV-2 could use the membrane protein angiotensin two converting enzyme (ACE2) as an entry receptor similarly to SARS-CoV (Wan et al., 2020; Li, 2013; Li et al., 2006; Hoffmann et al., 2020; Zhou et al., 2020).

Research on SARS-CoV-2 and COVID-19 is advancing at unprecedented speed. Much data has already been accumulated, some still in the pre-printing stage, that supports ongoing research aimed at understanding pathogenesis and provides information on potential therapeutic strategies. Here, we offer a critical summary of the current knowledge highlighting the remaining gaps that need to be filled to fully characterize the function of ACE2 in the infection by SARS-CoV-2 and the associated pathogenesis. Current evidence supports the low expression of ACE2 in the human respiratory system, which raises questions about the exact role of ACE2 in SARS-CoV-2 infection and has given rise to the hypothesis that co-receptors/attachment factors, such as neuropilins, heparan sulfate, and sialic acids or putative alternative receptors, such as CD147 and GRP78, could be involved in the entry of SARS-CoV-2 and contribute to tropism.

Evidence supporting ACE2 as an entry receptor for SARS-CoV-2

1.1 In-silico and in-vitro studies supporting interaction between ACE2 and SARS-CoV-2 spike protein

The surface glycoprotein S of coronaviruses mediating the attachment and entry into target cells is composed of 2 subunits, S1 and S2. The S1 subunit contains a N-terminal domain (NTD) and a receptor-binding domain (RBD) encompassing the receptor-binding motif (RBM) (Figure 1). The S2 contains a fusion peptide (FP), heptad repeat 1 (HR1) and 2 (HR2) domains, and a transmembrane (TM) and a cytoplasmic (CP) domain (Xia et al., 2020a; Li et al., 2005; Ou et al., 2020). After S1 binding to a membrane receptor, the FP is inserted into the cell membrane to promote fusion with the viral membrane, a process that depends on proteolytic cleavages at the S1/S2 site to separate S1 and S2 and at the S2 site to generate a mature FP (Hoffmann et al., 2018).

Figure 1

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After SARS-CoV outbreak in 2003, ACE2 was identified as the receptor for entry into lung epithelial cells (Li et al., 2003). Homologies between the RBD/RBM of SARS-CoV-2 and SARS-CoV led to the hypothesis that ACE2 could also serve as a receptor for SARS-CoV-2. RBDs share 75% similarities (Wan et al., 2020). Amino acid-based structure-function predictive framework analyses revealed similarities specifically in the hot spot regions responsible for the stability of SARS-CoV binding to ACE2 that may play a role in the zoonotic and human-to-human transmissions (Li, 2013; Li et al., 2006). However, 6 of the 14 amino acids of these hot spots differ in SARS-CoV-2 (L455, F486, Q493, S494, N501, and Y505). A plausible hypothesis is that these residues are the result of natural selection and may contribute to a greater affinity for human ACE2 (Wang et al., 2020c; Andersen et al., 2020).

Subsequent in-vitro studies, notably by resolution of cryo-EM structures, confirmed the structural similarities of the interaction between the S proteins of SARS-CoV and SARS-CoV-2 and ACE2, but also delineated further the divergences (Wan et al., 2020; Li, 2013; Li et al., 2006; Wrapp et al., 2020). The in-depth analysis of the interaction between the peptidase (PD) domain of ACE2 (19–615 aa) and the RBD of SARS-CoV (306–527 aa) highlighted the role of the amino acids involved in polar (A475, N487, E484, Y453), ionic (K417) and hydrophobic (Y489, F486) interactions and hydrogen bonds (G446, Y449, G496, Q498, T500, G502). On the other hand, these interactions are not engaged with the RBD of SARS-CoV-2 (319–541 aa) as predicted in part by the in-silico modeling (Wan et al., 2020; Wang et al., 2020a; Ortega et al., 2020). Additionally, the X-ray crystallographic structure of the PD domain (19–615 aa) in complex with the RBDs (319–541 aa) suggests the involvement of K417, G446, A475, and Q493 in the interaction with SARS-CoV-2, but not with SARS-CoV (Lan et al., 2020). A limitation of these studies is the use of ACE2 fragments lacking the C-terminal collectrin (CLD) and TM-like domains, which probably affects the interaction with the S protein. The cryo-EM analysis of the complete recombinant ACE2 suggests that the dimer coexists between an open and a closed state, while in the presence of the RBD of SARS-CoV-2 (319–541 aa) only the closed conformation is observed (Yan et al., 2020). This study also highlighted the involvement of K417 and G446 in the ACE2/SARS-CoV-2 interaction. As expected, one RBD domain interacted with the PD domain of one ACE2 monomer with an interface similar to the one found with SARS-CoV S (Wang et al., 2020a). The structure of the full-length SARS-CoV-2 S determined by Walls et al. also revealed open and closed conformational states, which were not observed using the 319–541 aa fragment (Yan et al., 2020; Walls et al., 2020). This structure also demonstrated the role of F486 and N501, which were predicted in silico, and of K417 in the interaction with ACE2 (Wan et al., 2020).

Several reports using surface plasmon resonance (SPR) to study the interaction between recombinant ACE2 and S proteins have determined a higher Kd for SARS-CoV S than for SARS-CoV-2 S (Table 1). Although these studies point to higher affinity of ACE2 for SARS-CoV-2 S than for SARS-CoV S, they are in contrast with results obtained using a biolayer interferometry binding (BLI) approach (Table 1). At this point, one cannot exclude that these discrepancies result from the analysis of distinct domains. Additionally, currently available measures rely only on protein fragments lacking the TM domains that likely alter the dynamics of the three-dimensional protein structure, prompting a careful interpretation of the available data.

Table 1

Reference	ACE2 protein PD domain	SARS-CoV S	SARS-CoV2 S	Method	Measured kd
Wrapp et al., 2020	1–615 aa	306–577 aa		SPR	325.8 nM
			1–1208 aa		14.7 nM
Wang et al., 2020a	19–615 aa	306–527 aa		SPR	408.7 nM
			319–541 aa		133.3 nM
Lan et al., 2020	19–615 aa	306–527 aa		SPR	31.6 nM
			319–541 aa		4.7 nM
Walls et al., 2020	1–614 aa	306–575 aa		BLI	1.2 nM
			328–533 aa		5 nM
Wrapp et al., 2020	1–615 aa	306–577 aa		BLI	13.7 nM
			319–591 aa		34.6 nM

Overall, in-silico predictions and structural analyses support an interaction between ACE2 and SARS-CoV-2 S with additional contact points compared to the interaction with SARS-CoV S, which are associated with a higher affinity that may explain the easy human-to-human spread (Wrapp et al., 2020). Future studies should aim to further characterize the interaction between full-length ACE2 and SARS-CoV-2 proteins to provide the most precise ground for the development of therapies aimed at disrupting this interaction.

1.2 In cellulo evidence of ACE2 acting as SARS-CoV-2 entry receptor

The extraordinary speed of research following the identification of SARS-CoV-2, particularly the development of pseudotyped viruses (Hoffmann et al., 2020; Ou et al., 2020; Walls et al., 2020; Tai et al., 2020; Lei et al., 2020a), the isolation of the virus from patient samples and the establishment of an in-vitro culture as early as January 2020 (Zhou et al., 2020), quickly made it possible to tackle the question of the identity of the entry receptor in cellular models (Hoffmann et al., 2020). Pseudotyped vesicular stomatitis virus expressing SARS-CoV-2 S (VSV-SARS-S2) efficiently infects only a limited number of cell lines, with Calu-3 human lung adenocarcinoma epithelial cell line, CaCo-2 human colorectal adenocarcinoma colon epithelial cell line and Vero African grey monkey kidney epithelial cell line being the most permissive (Hoffmann et al., 2020; Ou et al., 2020). While permissive cell lines all express ACE2, as previously demonstrated by indirect immunofluorescence (IF) or by immunoblotting (IB, antibody AF933) (Ren et al., 2006; Tseng et al., 2005; Liao et al., 2013; Lu et al., 2008), the role of ACE2 in virus entry was demonstrated by the observation that its ectopic expression is sufficient to make the BHK-21 fibroblast and HEK293 cell lines permissive to VSV-SARS-S2 (Hoffmann et al., 2020; Ou et al., 2020). Importantly, the preincubation of VSV-SARS-S2 with the soluble form of ACE2 prevents the infection likely by blocking the site of S protein interaction. The use of VSV pseudovirions expressing the SARS-CoV S protein (VSV-SARS-S) modified to contain the RBD from other coronaviruses, including MERS-CoV and SARS-CoV-2, allowed to underscore the importance of the RBD in the interaction with ACE2 in cellular models (Letko et al., 2020). Murine leukemia viruses (MLV)-based pseudoviruses expressing SARS-CoV and SARS-CoV-2 S were also found to infect Vero E6 cells (Walls et al., 2020), which express endogenous ACE2 (Sheahan et al., 2008), and ACE2-transfected BHK-21 cells (Walls et al., 2020).

Although pseudotyped viruses are a great tool to document the need for ACE2 for the entry steps mediated by the S protein, they do not make it possible to assess the contribution of other virions characteristics, such as envelope or membrane proteins, on the cell tropism (Joglekar and Sandoval, 2017). Access to SARS-CoV-2 patient isolates allowed to further evaluate the need of ACE2 for virus entry. Indeed, infection of HeLa, BHK-21 or A549 cells with isolates requires transfection of ACE2 (Hoffmann et al., 2020; Blanco-Melo et al., 2020; Zhou et al., 2020). While direct protein interaction in cellular model is difficult to assess, cell surface colocalization of ectopically expressed GFP-tagged ACE2 and SARS-CoV-2 S protein fragments containing the RBD was observed (Wang et al., 2020a). GFP-ACE2 expressed at the cell surface was also shown to bind soluble SARS-CoV-2 RBD; an interaction that was inhibited by incubation with a soluble form of ACE2 (Tai et al., 2020). Collectively, evidence obtained using cell lines further supports in-silico data that ACE2 binds to SARS-CoV-2 S and points to a model in which ACE2 is necessary for virus entry. More physiologically relevant studies are awaited to strengthen our understanding of the exact role of ACE2 in vivo and help determine if co-receptors or attachment factors act in concert with ACE2 and if alternative receptors may play a role in SARS-CoV-2 entry.

ACE2 expression in the respiratory apparatus

2.1 Basal expression of ACE2 in the human respiratory system

ACE2 was first identified in 2000 as a gene encoding a single isoform of a new angiotensin enzyme (Donoghue et al., 2000). Recently, due to the great interest generated around ACE2, bioinformatics and RNA-seq analyses have revisited the human ACE2 genomic region and identified the existence of an alternative splice site (Rehman and Tabish, 2020; Blume et al., 2020) that results in the transcription of a previously unknown isoform of ACE2 (deltaACE2 or dACE2). The dACE2 isoform lacks the first N-terminal 356 aa region compared to full-length ACE2 (flACE2) (Blume et al., 2020; Onabajo et al., 2020) and therefore is unable to bind to SARS-CoV-2 S (Onabajo et al., 2020). Considering the recent discovery of dACE2, the majority of ACE2 mRNA analyses reported below have not taken into account its existence. However, when possible, we indicated when the design discriminated specific ACE2 isoforms.

High-throughput gene promoter activity and mRNA expression data available in public repositories, that is functional annotation of the mammalian genome (FANTOM 5, flACE2), the Human Protein Atlas (HPA) and the genome‐based tissue expression consortia (GTEx), provide evidence of ACE2 mRNA expression in the respiratory system (Yu et al., 2015; Uhlén et al., 2015; Keen and Moore, 2015). As pointed out in two recent reports, levels of ACE2 mRNA in the respiratory system are low compared to other organs such as the small intestine, kidney or the myocardium (Table 2; Hikmet et al., 2020; Aguiar et al., 2020). An additional transcriptomic dataset of various human tissues confirmed ACE2 mRNA expression throughout the respiratory tract, including fetal and adult lungs, olfactory bulbs and trachea, with the highest expression in the lung (Leung et al., 2020). RNA-seq and microarray datasets from nasal and bronchial epithelial cells obtained through brushings demonstrate ACE2 detection with low levels in the nose, trachea and small and large airways (Leung et al., 2020; Su et al., 2004). Low expression of ACE2 (flACE2) in the nasal respiratory epithelium and at even lower levels in the trachea, bronchioles and alveoli was confirmed by RNA in-situ hybridization (RNA-ISH) of lung and nasal sections (n = 7) (Hou et al., 2020). RT-qPCR of brush samples from the same donors confirmed a gradient of ACE2 mRNA with the strongest expression in the nasal tissue and the lowest in the bronchioles and alveoli (Hou et al., 2020). It is noteworthy that this gradient of ACE2 expression mirrors the profile of permissiveness to SARS-CoV-2. Indeed, infection of primary cells led to higher viral titers in cells from the nasal epithelium and from the large airways than in cells from lower airways or Alveolar type II cells (AT2). Analysis of the specific expression of dACE2 and flACE2 in lung explants and nasal tissue reported similar expression profile at basal levels (Blume et al., 2020; Onabajo et al., 2020). Further analyses are needed to evaluate levels of expression of both isoforms in other respiratory tissues. While altogether these studies provide clues for ACE2 mRNA expression in the respiratory apparatus that is the primary target by SARS-CoV-2, they also shed light on the overall low levels detected at basal levels when performing bulk analyzes of the whole tissues (Figure 1).

Table 2

	Lung	Small Intestine	Kidney	Heart Muscle
HPA (pTPM)	1.7	31.1	107.2	31.1
GTEx (pTPM)	1.1	5.4	6.8	5.4
FANTOM5 (sTPM)	2.8	21.7	31.5	21.7

The low levels of ACE2 mRNA detected in tissues of the respiratory system likely reflects restricted expression in specific cell subpopulations (Figure 1). This has indeed been documented in several studies using scRNA-seq and snRNA-seq strategies, which make it possible to identify the cell populations expressing ACE2 mRNA. A first report describing the integrated analysis of 107 scRNA-seq and snRNA-seq datasets, including 22 from lungs and airways and 85 from other organs and encompassing 164 donors, revealed ACE2 expression in multi-ciliated epithelial and goblet cells of the proximal airways, and in AT2 cells in the distal lung epithelium (Muus et al., 2020). Expression of ACE2 in AT2 cells (defined as HTII280+ or PRO-SFTPC+ cells) was further confirmed by proximity ligation in-situ hybridization (PLISH) performed on airway and alveoli tissue from healthy donors. A second report describing the re-analysis of five scRNA-seq datasets from the lung, bronchus and nasal tissues, also concluded that ACE2 is enriched in lung AT2 cells and in bronchial and nasal ciliated epithelial and goblet cells (Hikmet et al., 2020). While the two reports led to similar qualitative conclusions, they differed in the quantitative report of the estimated % of ACE2+ AT2 cells, that is 6.2% and less than 1%, respectively. The use of the scRNA-ISH technique that combines scRNA-seq and ISH data, showed 20% of nasal and bronchial cells expressing ACE2 (Okochi et al., 2020). ACE2 mRNA was also detected in a fraction of nasal and bronchial ciliated (FOXJ1+) and secretory (MUC5B+) cells and in AT2 cells (SFTPC+) in the alveoli (Hou et al., 2020).

Several studies attempted to detect ACE2 protein by immunohistochemistry (IHC) in lung histological sections. Results exhibit more discrepancies than mRNA analyses, making it difficult to draw firm conclusions. Significant variations between studies are likely due to poor antibody validation practices, different antigen retrieval methodologies or to low antibody sensitivity. In Table 3, we attempted to summarize the available validation data for the antibodies used in the studies described in this review in accordance to the pillars defined by the Antibodypedia validation initiative (Uhlen et al., 2016). Importantly, all antibodies still await validation by siRNA or CRISPR technologies. Use of HPA000288 and MAB933 antibodies, which allow high detection of ACE2 in kidney and intestine, only showed very low to no detection in lung tissues (Uhlén et al., 2015; Hikmet et al., 2020). Positive staining of ACE2 was only observed in a very small percentage of individuals and corresponded to the surface of nasal ciliated cells, glandular cells of the trachea or AT2 cells consistent with mRNA expression. In a systematic study, six anti-ACE2 antibodies targeting different epitopes, ab15348, HPA000288, ab239924, NBP2-67692, AF933 and MAB933, were tested together with distinct antigen retrieval methods (Lee et al., 2020). Only the ab15348 antibody revealed robust staining in pneumocytes, while as expected the six antibodies showed positive staining in kidney and intestine. Further use of this antibody for indirect IF staining of only one donor revealed ACE2 detection in MUC1 positive type II pneumocytes. Additionally, IHC staining of resected lungs (n = 9) using this same antibody allowed detection of ACE2 in the small airway epithelial layer (Leung et al., 2020). ACE2 was detected in AT2 cells (PRO-SFTPC+) from human explant donors by IHC coupled to IF (IHC-IF) using the AF933, but not ab15348 or MAB933, antibodies, while low counts of ACE2-positive alveolar epithelial cells were detected in post-mortem lung sections (n = 10) using ab108252 (Ackermann et al., 2020; Muus et al., 2020).

Table 3

	Method	Antibodypedia	Provider	Additional information
Ab15348 (or GTX15348) Immunogen: 788-805aa	IB		+ Testis, intestines, lung, Calu-3 - Breast
	IHC		+ Testis, kidney, aorta and lung	+ Intestine, heart, stomach, spleen (Independent antibody validation) (Lee et al., 2020) +, +/-, - Lung. Increased in COPD and smokers (correlation with mRNA) (Leung et al., 2020; Muus et al., 2020; Lee et al., 2020)
	IF
MAB933 Immunogen: 18-74aa	IB		+ Kidney - NSO cells	+ Vero E6 cells - CHO cells (Jia et al., 2005)
	IHC		+ Kidney	+ Orthogonal (RNA) and independent antibody validation +/-, - Lung (Hikmet et al., 2020; Aguiar et al., 2020; Muus et al., 2020; Lee et al., 2020)
	IF			+ ALI-cultured ciliated airway epithelial cells (Martinez-Anton et al., 2013)
AF933 Immunogen: 18-74aa	IB		+ Ovary, testis and kidney	+ Airway and distal lung, ALI-cultured airway epithelial cells (correlation with mRNA levels), Calu-3 and Caco-2 cells (Liao et al., 2013; Smith et al., 2020) - A549 (expected), Huh-7 cells (Liao et al., 2013; Smith et al., 2020)
	IHC		+ Kidney	+ Testis, stomach, intestine (Independent antibody validation) +/-, - Lung (Ren et al., 2006; Muus et al., 2020; Lee et al., 2020)
	IF
HPA000288 Immunogen: 1-111aa	IB		+ Kidney, but several bands
	IHC		+ Intestine and kidney. - Tonsil	+ Orthogonal (RNA) and independent antibody validation +/-, - Lung (Uhlén et al., 2015; Hikmet et al., 2020; Lee et al., 2020)
	IF
Ab108252 Immunogen: 200-300aa	IB		+ Testis, kidney, lung, HepG2, Caco-2 - A549 cells
	IHC		+ Kidney
	IF
Ab239924 Immunogen: 200-300aa	IB		+ Testis, kidney	+ ACE2 transfected A459 - Non transfected A549 cells (Blanco-Melo et al., 2020)
	IHC		+ Testis, kidney	+ Intestine, heart, stomach, spleen (Independent antibody validation), +/- Lung (Lee et al., 2020)
	IF
NBP2-67692 Immunogen: 200-300aa	IB		+ Kidney
	IHC		+ Kidney	+ Testis and intestine (Independent antibody validation) - Lung (Lee et al., 2020)
	IF		+ HepG2, MCF-7, 293 cells
Anti-ACE2489 Immunogen: 489-508aa	IB		+ACE2 transfected CHO cells - Non transfected CHO cells
	IHC			+ Heart (No staining with secondary antibody alone) (Qian et al., 2013)
	IF
Sc-20998 Immunogen: 631-805aa	IB		Antibody discontinued	Detection in rat tissue only (Sims et al., 2005)
	IHC		Antibody discontinued
	IF		Antibody discontinued
Homemade antibody Immunogen: 206-225aa	IB			Detection in rat tissue only (Mossel et al., 2008)
	IHC
	IF

Overall, ACE2 protein is only weakly detected in the respiratory system by two distinct antibodies and a single antibody allows stronger detection in AT2 cells, while all antibodies detect high expression in kidneys and intestine. One cannot fully exclude that ACE2 detection in the lung is impaired by lung-specific post-translational modifications, such as glycosylations, that affects the antigen recognition. Bias from antibodies specificity and sensitivity can be circumvented through proteomic analyses. In this perspective, the low expression of ACE2 in the respiratory system is further supported by the analysis of public mass spectrometry (MS) datasets for protein abundance that does not show detectable ACE2 in the nasal mucosa or the lungs, in contrast to high levels in the kidneys and intestine (Hikmet et al., 2020). Altogether, currently available evidence from mRNA, IHC and MS analyses points to low expression of ACE2 in the respiratory apparatus at basal levels. How these low basal levels of ACE2 expression allow efficient replication and excretion of SARS-CoV-2 is a question that deserves more attention. Moreover, it is still difficult to conclude from the available data that the infection is strictly limited to ACE2 positive cells. These questions remain open and require further investigation.

2.2 ACE2 expression in human respiratory epithelial cells ex vivo: impact of differentiation

Ex vivo culture of cells from the respiratory system is an essential tool for the study of virus infection and pathogenesis. Epithelial cells from distinct sections of the respiratory tract, including the nose, trachea, bronchi and alveoli, are either cultured submerged in culture medium or at air-liquid interface (ALI) for polarization or differentiation into pseudostratified mucociliary epithelium. While submerged culture of human tracheobronchial epithelial cells exhibits low ACE2 mRNA and protein detection by IB(AF933 or MAB933), the expression levels are highly enhanced following differentiation in ALI (Blanco-Melo et al., 2020; Jia et al., 2005; Martinez-Anton et al., 2013; Smith et al., 2020; Qian et al., 2013). More recently, a clear distinction between dACE2 and flACE2 mRNA levels allowed to confirm that both isoforms are increased in differentiated cultures (Blume et al., 2020). Of note, re-submersion of cells, which led to loss of differentiation markers, reversed ACE2 mRNA and protein levels (Jia et al., 2005), supporting a key role of the differentiation process in ACE2 expression. Further study by IF staining of ALI-differentiated human primary alveolar cells (MAB933) showed that ACE2 is localized at the apical surface (Sims et al., 2005). This was recapitulated using confocal horizontal scanning (AF933) of the Calu-3 cell line polarized in ALI (Ren et al., 2006). Importantly, in hTERT-immortalized bronchial cells differentiated into multiciliated cells in ALI, only the flACE2 protein was detected in motile cilia (Blume et al., 2020) suggesting a specific role of the full-length isoform at this location. Overall, these studies show that differentiation significantly increases the expression of ACE2 and, as such, suggests that the use of differentiated cells should be preferred to model ACE2-dependent SARS-CoV-2 infection. Additionally, the heterogeneity of patient-derived respiratory epithelial cells argues for the study of large cohorts to reach clear conclusions. However, this is hardly achievable due to the scarcity of the cells and the high demanding differentiation process. Beside donor to donor variation, IF staining of ALI-cultured AT2 cells also pointed to heterogeneous ACE2 levels in a single culture (Mossel et al., 2008), which correlates with observations made on lung tissue sections showing ACE2 in only a small fraction of the AT2 cells (Muus et al., 2020).

2.3 ACE2 levels during SARS-CoV-2 infection

The correlation between the expression of ACE2 mRNA and that of the classical interferon (IFN) stimulated genes (ISG) that was observed through meta-analysis of scRNA-seq data, as well as the presence of two STAT1 binding sites in the promoter of the human ACE2 gene, supports the hypothesis that ACE2 itself could be an ISG (Ziegler et al., 2020; Hennighausen and Lee, 2020). Several reports have indeed documented the capacity of IFNβ and/or IFNα2 to induce ACE2 mRNA in human basal epithelial cells from nasal scraping, human tracheal cells and human large and small airway cells (Hou et al., 2020; Smith et al., 2020; Ziegler et al., 2020). FlACE2 was also induced in nasal and tracheal cells, but not in small airway cells, in response to IFNγ (Smith et al., 2020). Specific analysis of flACE2 and dACE2 isoforms revealed that in fact IFNα, IFNβ and IFN-λ3 specifically induce dACE2 in human bronchial epithelial cells (HBEC) (Blume et al., 2020; Onabajo et al., 2020). While an increase of dACE2, which does not bind to SARS-CoV-2 S, should not translate into more entry of the virus, the question of how this increase would impact the host antiviral response remains to be determined. The IFN-dependent regulation of ACE2 mRNA expression might explain ACE2 upregulation observed within bystander goblet or squamous cells, but not directly in infected cells, during influenza (IAV) virus infections (Ziegler et al., 2020). Only dACE2 mRNA is upregulated upon IAV and rhinovirus infections, but the role of IFNs in ACE2 upregulation in these contexts remains to be fully addressed (Onabajo et al., 2020).

Converging evidence indicates that ACE2 mRNA levels are also increased during SARS-CoV-2 infection. In a study with a limited cohort, scRNA-seq analysis of nasopharyngeal swabs, bronchial brushes and bronchoalveolar lavages showed up to 3-fold upregulation of ACE2 mRNA in COVID-19 patients (n = 9) compared to healthy individuals (n = 2). ACE2 mRNA induction was observed in secretory and ciliated cells, which also exhibited the most SARS-CoV-2+ cells (Chua et al., 2020). In ALI-differentiated HBEC, SARS-CoV-2-induced ACE2 mRNA is observed in ciliated, basal club and an intermediate between basal cells and club (BC/Club) infected and bystander cells (Ravindra et al., 2020). Surprisingly, this result was not corroborated in the Calu-3 and differentiated BCi-NS1.1 respiratory cell line models, in which neither flACE2 nor dACE2 were induced by SARS-CoV-2 (Blume et al., 2020; Onabajo et al., 2020). This contrasts with the specific induction of dACE2 observed in the non-respiratory Caco-2 cell line (Onabajo et al., 2020). A role of IFNs in the upregulation of ACE2 by SARS-CoV-2 is difficult to conclude based on the current evidence for the status of IFN production and signaling during SARS-CoV-2 infection. In differentiated HBEC, induction of IFNβ and IFNλ mRNA was observed in infected cells, but not in the bystander cells (Ravindra et al., 2020). Increased mRNA levels of IFNβ and IFNλ1 and 3 were also observed in infected Calu-3 cells (Sun et al., 2020; Lei et al., 2020b; Banerjee et al., 2020). This contrasts with the lack of detectable IFNβ or IFNλ1–3 mRNA observed in submerged culture of HBEC upon SARS-CoV-2 infection (Blanco-Melo et al., 2020; Vanderheiden et al., 2020). In an ex vivo human lung explant model, SARS-CoV-2 infection also failed to induce detectable levels of IFNα, β, γ, or λ1–3 at any time point for up to 48 hr, while SARS-CoV induced IFNα, β, γ, or λ1–3 at late time points (Chu et al., 2020). These discrepancies could be due to differences in MOI and time course of the infection, but also from the quality of virus preparation as the content of defective virus particles is known to trigger IFN production in the context of other virus infections (Vignuzzi and López, 2019). Systematic analysis of the impact of these parameters will be necessary to resolve the status of IFN induction by SARS-CoV-2 in respiratory epithelial cells. IFNs plasma levels in COVID-19 patients have also started to be documented. In a first study of critically ill COVID-19 patients, IFN-α2, but neither IFNβ nor IFNλ, was detected in the plasma of 21 out of 26 patients with a peak 10 days after onset of symptoms (Trouillet-Assant et al., 2020). This is in line with a deep analysis of type I IFN mRNA regulation in COVID-19 patients at different stages of the disease. While no IFNβ mRNA and protein were detected in the plasma regardless of the severity of illness (n = 32) compared to healthy donors (n = 13), IFNα mRNA was found in the plasma of all COVID-19 patients (Hadjadj et al., 2020). In two separate reports, plasma levels of IFNα were lower in critically ill patients than in patients with mild to moderate COVID-19 (n = 11 and 10) (Banerjee et al., 2020; Hadjadj et al., 2020). In addition, IFNα levels were maintained in mild to moderate patients for up to 17 days, but decreased in severe and the critically ill patients after 10 and 13 days, respectively (Hadjadj et al., 2020). In addition to evidence supporting weak and shortened levels of IFNα by SARS-CoV-2 infection in critically ill COVID-19 patients, molecular data have started to document the capacity of SARS-CoV-2 to evade the IFN response as previously documented for SARS-CoV (Lei et al., 2020b; Park and Iwasaki, 2020; Xia et al., 2020b). The first evidence results from the overexpression of SARS-CoV-2 proteins in HEK293T cells before infection with Sendai virus or expression of constitutively active RIG-I or MDA5 receptors. Results diverged among the two available reports, but Nsp1, Nsp13, and Orf6 were consistently found to inhibit IFNβ promoter induction and IFN signaling (Lei et al., 2020b; Xia et al., 2020b). The mechanisms underlying these inhibitions are not fully defined, but Nsp13 appears to act upstream of TBK1 phosphorylation, while Orf6 interferes with IRF3 and STAT1 nuclear translocation. A truncation variant of SARS-CoV-2 Orf3b is also thought to be associated with inhibition of IFNβ production (USFQ-COVID19 Consortium et al., 2020). In contrast to the impact of SARS-CoV-2 protein overexpression, SARS-CoV-2 infection of Calu-3 cells, failed to hinder IFNβ induced phosphorylation of STAT1 and STAT2 and downstream IFIT1 production (Banerjee et al., 2020). In summary, the full scope of the interplay between SARS-CoV-2 and the IFN response remains to be carefully characterized before conclusion about the impact on ACE2 induction can be drawn.

Studies documenting ACE2 protein expression upon IFNs stimulation and SARS-CoV-2 infection are really sparse. Immunoblot analysis of ACE2 (AF933) in fully differentiated HBEC derived from asthmatic patients stimulated with IFNγ showed slight increase in only 1 out of 4 donors (Ziegler et al., 2020). In contrast, SARS-CoV-2 infection (MOI of 2) of A549 cells transfected with ACE2 showed decreased levels (ab239924) at 24 hr post-infection (Blanco-Melo et al., 2020). While this is a preliminary observation that needs to be further confirmed, it is in line with the observation that SARS-CoV infection of Vero E6 cells led to downregulation of ACE2 protein levels, which inversely correlated with viral replication (Glowacka et al., 2010). The observation that ACE2 mRNA levels increase or remain stable while the protein levels are decreased during SARS-CoV-2 infection suggests a post-transcriptional regulation mechanism, such as degradation or a halt in the translation. The exact mechanism(s) underlying this dual regulation remains to be investigated to fully comprehend how cells respond to SARS-CoV-2 infection and the potential role of ACE2. These results contrast with the post-mortem examination of lungs from deceased COVID-19 patients (n = 7) compared to age-matched uninfected individuals (n = 10) by IHC (ab108252) which showed a significantly greater number of ACE2-positive alveolar epithelial cells in COVID-19 individuals compared to controls (Ackermann et al., 2020).

Altogether, for the time being, it appears clear that ACE2 mRNA is detected in the respiratory system, but at significantly lower levels than in kidneys and intestine. Detection of ACE2 protein remains controversial mainly because of discrepancies between antibodies. Importantly, we now know that there are 2 isoforms of ACE2, one of which is unable to bind to SARS-CoV-2. Future studies aimed at analyzing ACE2 mRNA and protein should attempt to determine which of the isoforms is detected considering the great impact this information will have on our understanding of SARS-CoV-2 infection and tropism. The distribution in respiratory tissues is heterogenous and ACE2 is mainly detected in ciliated, goblet, and club cells of the nose and bronchi and in the AT2 cells in the alveoli (Figure 1). The detection of ACE2 mainly in nasal cells could explain a higher shedding of virus in the upper respiratory tract at the beginning of the disease, which has been observed from repeated biological samples (Wang et al., 2020b; Zou et al., 2020). Conversely, the presence of ACE2 in AT2 might facilitate entry of SARS-CoV-2 as observed in infected macaques (Rockx et al., 2020) causing damages of alveoli that could contribute to COVID-19 severity (Olajuyin et al., 2019). Future studies should aim to determine if and how regulation of ACE2 expression during SARS-CoV-2 infection impacts the dynamics of infection and the antiviral response.

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Author details

1. Natalia Zamorano Cuervo

   CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9199-9654

2. Nathalie Grandvaux

   1. CRCHUM - Centre Hospitalier de l’Université de Montréal, Québec, Canada
   2. Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada

   For correspondence

   nathalie.grandvaux@umontreal.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0567-0284

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