1 SARS-CoV-2 strategically mimics proteolytic activation

2 of human ENaC
3
4
5
1 2 2, 2,
Praveen Anand , Arjun Puranik , Murali Aravamudan, AJ Venkatakrishnan *, Venky Soundararajan *
6 1
nference Labs, Murugesh Pallya, Bengaluru, Karnataka 560047, India
7 2
nference, inc, One Main Street, East Arcade, Cambridge, MA 02142, USA
8 * Address correspondence to AJV (aj@nference.net) or VS (venky@nference.net)

9 Abstract

10 Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host

11 cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site,
12 absent in any previous coronavirus sequenced, resulting in striking mimicry of an identical
13 FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic
14 alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN
15 site is critical for activation of ENaC. Single cell RNA-seq from 65 studies shows significant
16 overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the
17 cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular
18 characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy
19 wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be
20 driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway
21 surface liquid, whose misregulation is associated with respiratory conditions.

22 Introduction

23 The surface of SARS-CoV-2 virions is coated with the spike (S) glycoprotein, whose
24 proteolysis is key to the infection lifecycle. After the initial interaction of the S-protein with the
25 ACE2 receptor (Walls et al., 2020), host cell entry is mediated by two key proteolytic steps. The
26 S1 subunit of the S-protein engages ACE2, and viral entry into the host cell is facilitated by
27 proteases that catalyze S1/S2 cleavage (Belouzard et al., 2012, 2009) at Arginine-667/Serine-
28 668 (Figure 1a). This is followed by S2’ site cleavage that is required for fusion of viral-host cell
29 membranes (Hoffmann et al., 2020; Walls et al., 2020).
30
31 Results
32 We hypothesized that the virus may mimic host substrates in order to achieve
33 proteolysis. Comparing human-infecting SARS-CoV-2 with SARS-CoV strains, as well as with
34 candidates of zoonotic origin (Pangolin-CoV and Bat-CoV RaTG13), shows that SARS-CoV-2
35 has evolved a unique sequence insertion at the S1/S2 site (Zhang et al., 2020) (Figure 1a).
36 Although the S protein of SARS-CoV-2 shares high sequence identity with the S proteins of
37 Pangolin-CoV (92%) and Bat-CoV RaTG13 (97%), the furin insertion site seems to be uniquely
38 acquired by SARS-CoV-2. The resulting tribasic 8-mer peptide (RRARSVAS) on the SARS-
39 CoV-2 S1/S2 site is conserved among 10,956 of 10,967 circulating strains deposited at GISAID
40 (Elbe and Buckland-Merrett, 2017), as of April 28, 2020 (Supplementary file 1a). This peptide
41 is also absent in over 13,000 non-COVID-19 coronavirus S-proteins from the VIPR database
42 (Carrillo-Tripp et al., 2009). Strikingly, examining over 10 million peptides (8-mers) of 20,350
43 canonical human proteins from UniProtKB shows that the peptide of interest (RRARSVAS) is
44 present exclusively in human ENaC-ɑ, also known as SCNN1A (p-value = 4E-4) (see Materials
45 and Methods). The location of this SARS-CoV-2 mimicked peptide in the ENaC-ɑ structure is in

1
46 the extracellular domain (Noreng et al., 2018) (Figure 1b). This suggests that the SARS-CoV-2
47 may have specifically evolved to mimic a human protease substrate.
48 ENaC regulates sodium ion (Na+) and water homeostasis and ENaC’s expression levels
49 are controlled by aldosterone and the associated Renin-Angiotensin-Aldosterone System
50 (RAAS)6. In distal lung airways, ENaC is known to play a key role in controlling fluid
51 reabsorption at the air-liquid interface (Rossier and Stutts, 2009), and similar to SARS-CoV2,
52 ENaC-ɑ also needs to be proteolytically activated for its function (Vallet et al., 1997). FURIN
53 cleaves the equivalent peptide on mouse ENaC-ɑ between the Arginine and Serine residues in
54 the 4th and 5th positions respectively (RSAR|SASS) (Hughey et al., 2004a, 2004b), akin to the
55 recent report establishing FURIN cleavage at the S1/S2 site of SARS-CoV-2 (Walls et al., 2020)
56 (Figure 1b). It is conceivable that human ENaC activation may be compromised in SARS-CoV-
57 2 infected cells, for instance by SARS-CoV-2 exploiting host FURIN for its own activation. The
58 likely consequence would be low ENaC activity on the surface of the airways leading to
59 compromised fluid reabsorption(Planès et al., 2010; Yurdakök, 2010), an important lung
60 pathology in COVID-19 patients with acute respiratory distress syndrome (ARDS). Indeed, the
61 exact mechanism of SARS-CoV-2’s potential impact of ENaC activation needs to be
62 investigated.
63 Although the furin-like cleavage motifs can be found in other viruses (Coutard et al.,
64 2020), the exact mimicry of human ENaC-ɑ cleavage site raises the specter that SARS-CoV-2
65 may be hijacking the protease network of ENaC-ɑ for viral activation. We asked whether there is
66 an overlap between putative SARS-CoV-2 infecting cells and ENaC-ɑ expressing cells.
67 Systematic single cell expression profiling of the ACE2 receptor and ENaC-ɑ was performed
68 across human and mouse samples comprising ~1.3 million cells (Venkatakrishnan et al., 2020)
69 (Figure 1c). Interestingly, ENaC-ɑ is expressed in the nasal epithelial cells, type II alveolar cells
70 of the lung, tongue keratinocytes, and colon enterocytes (Figure 1c and Figure 2-figure
71 supplements 1-6), which are all implicated in COVID-19 pathophysiology (Shweta et al., 2020;
72 Venkatakrishnan et al., 2020). Further, ACE2 and ENaC-ɑ are known to be expressed generally
73 in the apical membranes of polarized epithelial cells (Butterworth, 2010; Musante et al., 2019).
74 The overlap of the cell-types expressing ACE2 and ENaC-ɑ, and similar spatial distributions at
75 the apical surfaces, suggest that SARS-CoV-2 may be leveraging the protease network
76 responsible for ENaC cleavage.
77 Beyond FURIN that cleaves the S1/S2 site (Walls et al., 2020), we were intrigued by the
78 possibility of other host proteases also being exploited by SARS-CoV-2. We created a 160-
79 dimensional vector space (20 amino acids x 8 positions on the peptide) for assessment of
80 cleavage similarities between the 178 human proteases with biochemical validation from the
81 MEROPS database (see Materials and Methods; 0 < protease similarity metric < 1) (Rawlings
82 et al., 2018). This shows that FURIN (PCSK3) has overall proteolytic similarity to select PCSK
83 family members, specifically PCSK5 (0.99), PCSK7 (0.99), PCSK6 (0.99), PCSK4 (0.98), and
84 PCSK2 (0.94) (Supplementary File 1b). It is also known that the protease PLG cleaves the ɣ-
85 subunit of ENaC (ENaC-ɣ)(Passero et al., 2008).
86 In order to extrapolate the tissue tropism of SARS-CoV-2 from the lens of the host
87 proteolytic network, we assessed the co-expression of these proteases concomitant with the
88 viral receptor ACE2 and ENaC-ɑ (Figure 2). This analysis shows that FURIN is expressed with
89 ACE2 and ENaC-ɑ in the colon (immature enterocytes, transit amplifying cells) and pancreas
90 (ductal cells, acinar cells) of human tissues, as well as tongue (keratinocytes) of mouse tissues.
91 PCSK5 and PCSK7 are broadly expressed across multiple cell types with ACE2 and ENaC-ɑ,
92 making it a plausible broad-spectrum protease that may cleave the S1/S2 site. In humans,
93 concomitant with ACE2 and ENaC-ɑ, PCSK6 appears to be expressed in cells from the
94 intestines, pancreas, and lungs, whereas PCSK2 is noted to be co-expressed in the respiratory

1
 95 tract and the pancreas (Figure 2). It is worth noting that the extracellular proteases need not
96 necessarily be expressed in the same cells as ACE2 and ENaC-ɑ. Among the PCSK family
97 members with the potential to cleave the mimicked 8-mer peptide, it is intriguing that the same
98 tissue can house multiple proteases and also that multiple tissues do share the same set of
99 proteases.
100
101 Discussion
102 Our findings emphasize that redundancy may be wired into the mechanisms of host
103 proteolytic activation of SARS-CoV-2. This study should stimulate the design of experiments
104 that confirm the working hypothesis generated by our unbiased and systematic computational
105 analysis. The mimicry of a cleavable host peptide central to pulmonary, renal, and
106 cardiovascular function provides a new perspective to the evolution of SARS-CoV-2 as the first
107 coronavirus pandemic.

1
108 Materials and methods
109
110 Alignment of coronavirus spike proteins
111 The complete S-protein sequence for SARS-CoV (Uniprot ID: P59594) and SARS-CoV-
112 2 was obtained from uniprot (ftp://ftp.uniprot.org/pub/databases/uniprot/pre_release/). The
113 sequences of Pangolin-CoV and Bat-CoV RaTG13 were obtained from the VIPR database
114 (https://www.viprbrc.org/). Sequence alignments using Clustal-W, and comparison of SARS-
115 CoV-2 versus other coronavirus strains were performed using JalView17.

116 Analysis of 8-mers of the human proteome

117 The number of 8-mers in Uniprot 20,350 reference sequences are 10,257,893 (10.26M).
118 The previously identified SARS-CoV-2 8-mer ‘RRARSVAS’ was in fact found in a Uniprot
119 reference sequence (p-value ≈ 10.26M/208 = 4E-4; chance of finding that particular 8-mer
120 anywhere in the reference sequences).
121
122 Calculating the cosine similarity metric for protease cleavage site
123 The position frequency matrix (PFM) of the individual proteases obtained from the
124 MEROPS database (Rawlings et al., 2018) was converted to a probability weight matrix (PWM)
125 (normalized and scaled) (Supplementary File 1b). Out of 178 proteases, there were 146
126 proteases that had specificity information available on the 8 mer peptide spanning the cleavage
127 site (±4). The 20 (amino acids) x 8 (position) matrix defined for each of the proteases were
128 flattened into a single vector with 160 elements. We performed a cosine similarity calculation
129 between all pairs (X,Y) of protease specificity vector. The similarity was derived as the
130 normalized dot product of X and Y : K(X, Y) = <X, Y> / (||X||*||Y||)).

131 Overlap of cell types expressing ENaC-ɑ, ACE2 and proteases from scRNA-seq datasets
132 We performed a systematic expression profiling of the ACE2 and ENaC-ɑ across 65
133 published human and mouse single-cell studies comprising ~1.3 million cells using nferX Single
134 Cell platform (Supplementary File 1c, https://academia.nferx.com/) (Venkatakrishnan et al.,
135 2020). The ACE2 expression could be detected in 67 studies (59 studies of human samples and
136 8 studies of mouse samples) spanning across ~50 tissues, over 450 cell-types and ~1.05 million
137 cells. In order to call a given cell-type to be positive for both ACE2 and a protease we applied a
138 cutoff of 1% of the cells in the total cell-type cluster population to have a non-zero count
139 associated with both ACE2 and the respective protease. The mean expression of the proteases,
140 ENaC-ɑ and ACE2 was derived for individual cell population within each of the studies. The cell-
141 type information was obtained from the author annotations provided for each of the studies. The
142 analysis was performed separately on the mouse and human datasets. For each protease, the
143 mean expression of in a given cell-population (mean log[cp10k +1] counts) was Z-score
144 normalized (to ensure the sd=1 and mean ~0 for all the genes) to obtain relative expression
145 profiles across all the samples. The same normalization was applied to ACE2 and ENaC-ɑ and
146 both human and mouse datasets were analyzed independently by generating heatmaps. The
147 cell types having zero-expression values of ACE2 were also included as negative control to
148 probe the expression of various proteases.
149 We performed an analysis to identify the cell types with significant overlap of ACE2 and
150 ENaC-ɑ expression. To this end, we shortlisted cell types in which ENaC-ɑ is expressed in a
151 significantly higher proportion of ACE2-expressing cells than in the overall population of cells of
152 that sub-type. We computed the ratios of these proportions, and used a corresponding Fisher
153 exact test to compute significance.
154

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155 Acknowledgements
156 The authors thank Patrick Lenehan, David Zemmour, Travis Hughes, Tyler Wagner, and Mathai
157 Mammen for their careful review and feedback. The authors are also grateful to Ramakrishna
158 Chilaka for the software visualization tools, and Dhruti Patwardhan, Saranya Marimuthu, Jaya
159 Jain, Dariusz Murakowski, and Enrique Garcia-Rivera for their assistance with databases.
160
161
162 Figure and Supplementary file Legends
163
164 Figure 1. Targeted molecular mimicry by SARS-CoV-2 of human ENaC-ɑ and profiling
165 ACE2-FURIN-ENaC-ɑ co-expression. (a) The cartoon representation of the S-protein
166 homotrimer from SARS-CoV-2 is shown (PDB ID: 6VSB). One of the monomers in highlighted
167 red. The alignment of the S1/S2 cleavage site required for the activation of SARS-CoV-2,
168 SARS-CoV, Pangolin-CoV and Bat-CoV RaTG13 are shown. The 4 amino acid insertion
169 evolved by SARS-CoV-2, along with the abutting cleavage site is shown in a box. (b) The
170 cartoon representation of human ENaC protein is depicted (PDB ID: 6BQN; chain in green),
171 highlighting the ENaC-ɑ chain in green. The alignment on the right captures FURIN cleavage at
172 the S1/S2 site of SARS-CoV-2, along with its striking molecular mimicry of the identical peptide
173 from human ENaC-ɑ protein (circled in the cartoon rendering of human ENaC). The alignment
174 further shows the equivalent 8-mer peptide of mouse ENaC-ɑ that is also known to be cleaved
175 by FURIN. One of the known genetic alterations on human ENaC-ɑ is highlighted as well
176 (Welzel et al., 2013). (c) The single cell transcriptomic co-expression of ACE2, ENaC-ɑ, and
177 FURIN is summarized. The heatmap depicts the mean relative expression of each gene across
178 the identified cell populations. The human and mouse single cell RNA-seq are visualized
179 independently. The cell types are ranked based on decreasing expression of ACE2. The box
180 highlights the ACE2 positive cell types in human and mouse samples.
181
182 Figure 2. Expression profiling of identified proteases. The heatmap depicts the relative
183 expression of ACE2 and ENaC-ɑ along with a list of proteases that can potentially cleave the
184 S1/S2 site. The relative expression levels are denoted on a scale of blue (low) to red (high). The
185 rows denote proteases and columns denote cell-types.
186
187 Figure 2-figure supplement 1. Cardiomyocytes express ENaC-ɑ (SCNN1A) and ACE2
188 (Primary data processed from Pubmed ID:31915373 and hosted on
189 https://academia.nferx.com/)
190
191 Figure 2-figure supplement 2. Type-II Alveolar Cells of the lungs express ENaC-ɑ (SCNN1A)
192 and ACE2 (Primary data processed from Pubmed ID: 31892341 and hosted on
193 https://academia.nferx.com/)
194
195 Figure 2-figure supplement 3. Goblet cells and Ciliated cells of the nasal epithelial layer
196 express SCNN1A (ENaC-ɑ) and ACE2 (Primary data processed from Pubmed ID: 32327758
197 and hosted on https://academia.nferx.com/)
198

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199 Figure 2-figure supplement 4. Tongue keratinocytes express SCNN1A (ENaC-ɑ) and ACE2
200 (Primary data processed from Pubmed ID:30283141 and hosted on
201 https://academia.nferx.com/)
202
203 Figure 2-figure supplement 5. Higher expression of SCNN1A was detected in 58% of the
204 principal cells in the collecting duct 47% of the connecting tubule cells from the kidney, but
205 ACE2 expression was not detected in these cell types. Although only 2.77% of the proximal
206 tubule cells had detectable expression of SCNN1A, a higher percentage (8.46%) of these cells
207 were also observed to express ACE2. (Primary data processed from Pubmed ID: 31604275 and
208 hosted on https://academia.nferx.com/)
209
210 Figure 2-figure supplement 6. Colon enterocytes express SCNN1A (ENaC-ɑ) and ACE2
211 (Primary data processed from Pubmed ID:31348891 and hosted on
212 https://academia.nferx.com/)
213
214 Supplementary file 1a. SARS-CoV-2 variants in the RRARSVAS 8-mer peptide from 10,987
215 spike (S) protein sequences of the GISAID database. The specific variations are highlighted in
216 Red.
217 Supplementary file 1b. Protease cleavage propensities for FURIN and the other proteases identified
218 as similar from the vector space analysis conducted. Similarity (FURIN) ranges from 0 to 1. Highlighted
219 green are amino acids occurring in greater than 10% of the cleaved substrates at that position (compiled
220 from MEROPS).
221 Supplementary file 1c. List of single-cell studies analyzed and incorporated into the nferX
222 resource (https://academia.nferx.com/)
223
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a SARS-CoV-2 S1/S2 insertion c Profiling proteases for S1/S2 cleavage via Single Cell RNA-seq
S1/S2 cleavage site

R686 S687
SARS-CoV-2 Q T N S P R R A R S V A S Q S
-α
677 691 -α aC

IN
aC

in
EN

E2

e2
R
EN

r
ACE2+,ENaC-α+,FURIN+

fu
ace2+,ENaC-α+,furin+

FU

ac
AC
cell-types
SARS-CoV V S L L - - - - R S T S Q K S proximal tubule cells
cell-types

663 673 (kidney;study10)

ace2+ cell types

enterocytes epithelial cells

ACE2+ cell types

S1/S2 (small intestine;study19) (colon; study2)
site Pangolin-CoV M S S F - - - - R S V N Q R S cardiomyocytes Keratino cytes
(heart;study22) (tongue; study2)
6 77 6 87
epithelial cells
S protein (nasal cavity;study27)
epithelial cells
Bat-CoV RaTG13 Q T N S - - - - R S V A S Q S (respiratory tract;study27)
6 77 6 87 best4+ enterocytes
SARS-CoV-2 (colon;study3)
cycling transit amplifying
cells
(colon;study3)
enterocytes
b Mimicked cleavage of SARS-CoV-2/ENAC-α by FURIN (colon;study3)
goblet cells
(colon;study3)
immature enterocytes 1
FURIN (colon;study3)
immature enterocytes 2
SARS- (colon;study3)

ACE2- cell types

RRARSVAS

ACE2- cell types

CoV-2 transit amplifying cells 2
S1/S2 683 690 (colon;study3)
t cells
(small intestine jejunum;
Human RRARSVAS study46)

ENaC-α 201 * 208 alveolar type2

(lung;study68)

Mouse RSARSASS
ENaC-α 238 245 Relative Relative
expression expression
FURIN
High High

human ENaC-α
*Frameshift mutation resulting in S205X trucation
Low Low
causing Pseudohypoaldosteronism type 1 (PHA 1)
 Small and large
intestine Lung

-α
-α

PC K4
PC K5
PC K6

PC K4
PC K5
PC K6
PC 2

PC 2
7

7
PC IN

PC IN
aC
SK

SK
E2

SK

E2

SK
aC

S
S
S

S
S
S
R

R
EN
AC

AC
FU

FU
EN

Human
enterocyte (rectum;study83) epithelial_cells (respiratory_tract; study27)
enterocytes (small_intestine;study19)
enterocytes (colon;study3) alveolar_type2 (lung; study68)
immature_enterocytes_1 (colon;study3) fibroblasts (lung; study7)
t_cells (small_intestine_jejunum;study46)
Human

immature_enterocytes_2 (colon;study3) epithelial cells (trachea; study2)

Mouse
transit_amplifying_cells_2 (colon;study3)
goblet_cells (small_intestine;study19) smooth muscle cells (lung; study15)
cycling_transit_amplifying_cells (colon;study3)
best4+_enterocytes (colon;study3)
goblet_cells (colon;study3)
paneth_cells (small_intestine_duodenum;study39)
fibroblasts (small_intestine_duodenum;study39)
Mouse

epithelial cells (colon; study2)

-α

PC K4
PC K5
PC K6
PC 2

7
PC IN
goblet cells (small_intestine;study1)

aC

SK
E2

SK
S
S
S
Kidney

R
EN
AC

FU
proximal_tubule_cells (kidney; study10)

Human
pelvic_epithelial_cells (kidney; study10)
podocytes (kidney; study9)
PC K4
PC K5
PC K6
PC 2
-α

7
PC IN
SK
E2

SK

Pancreas
aC

S
S
S
R
AC

FU
EN
Human

pancreatic ductal cells (pancreas; study13)

pancreatic acinar cells (pancreas; study13)

-α

PC K4
PC K5
PC K6
PC 2

7
PC IN
endothelial (pancreas; study52)

SK
E2

SK
aC
Heart

S
S
S
R
AC

FU
EN
Human
cardiomyocytes (heart;study22)

-α

PC K4
PC K5
PC K6
-α

PC 2
PC K4
PC K5
PC K6
PC 2

7
PC IN
7
PC IN

SK
E2
SK

SK
aC
E2

SK
aC

S
S
S
R
S
S
S
R

Nasal cavity Tongue

AC

FU
AC

EN
FU
EN
Human

epithelial cells (nasal cavity; study 27) keratinocytes (tongue; study2) High
Mouse

mast cells (nasal cavity; study27) epidermal basal cells (tongue; study2)

Low
 Among the cells selected from this study, ACE2 is not appreciably expressed

card Expression in cardiomyocytes

Signals Percent of
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
to (Counts Per 10K) of Cells expression
to Cell
Tissue >0
Expression of ACE2 In Individual Cell Populations
1 Tissue , 6 Cell Populations , 14.9K Cells
heart Cardiomyocytes 7670 1.17
ENAC-⍺

Signals Percent
Rows per page: 5 of
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
to (Counts Per 10K) of Cells expression
to Cell
Tissue >0

Expression of SCNN1A Across Selected Cell Populations

heart Cardiomyocytes 7670 7.97
ACE2 1 Tissue , 6 Cell Populations , 14.9K Cells
 Among the cells selected from this study, ACE2 is not appreciably expressed

type2 Expression in Type-II alveolar cells of lungs

Signals Percent of
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
to (Counts Per 10K) of Cells expression
to Cell
Tissue >0

Expression of ACE2 In Individual Cell Populations

Alveolar 1 Tissue , 25 Cell Populations , 57K Cells
Lung 4676 50.04
Type2
ENAC-⍺
type2

Signals Percent5 of
Rows per page:
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
to (Counts Per 10K) of Cells expression
to Cell
Tissue >0

Alveolar
Expression of SCNN1A Across Selected Cell Populations
ACE2 Lung
Type2 1 Tissue , 25 Cell Populations , 57K Cells 4676 1.69
 Signals Percent of
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
to (Counts Per 10K) of Cells expression
to Cell
Tissue >0
Expression of SCNN1A In Individual Cell Populations
Goblet 1 Tissue , 12 Cell Populations , 7.1K Cells
NasalEpithelium 4017 83.1
1
goblet 2

21/05/2020 Signals Single Cell Percent5 of

Rows per page:
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
to (Counts Per 10K) of Cells expression
to Cell
Tissue >0

ENAC-⍺ Summary of ACE2 Expression

Goblet
What genes have a similar expression
NasalEpithelium
Expression of SCNN1A Across Selected Cell Populations
profile in this study? 1463 71.84
2 1 Tissue , 12 Cell Populations , 7.1K Cells
Among the cells selected from this study, ACE2 is highly expressed in:
Nasalepithelium: Club
21/05/2020 Single Cell Rows per page: 5
https://preview.nferx.com/singlecell/home?view=study_explorer&token=scnn1a&study=study85&studyType=human&corpus=corpus&plotBy=DisplayName&dataValue=Umap&tissueType=""&sc=df&gene=SCNN1A

Summary of ACE2 Expression

Expression of SCNN1A
Expression of ACE2 Across
What genes have a similar expression profile in this study?
Selected
In Individual CellCell Populations
Populations
1
1 Tissue
Tissue ,, 12
12 Cell
Cell Populations
Populations ,, 7.1K
7.1K Cells
Cells
Among the cells selected from this study, ACE2 is highly expressed in:
Nasalepithelium: Club
21/05/2020 Goblet_ Single Cell
https://preview.nferx.com/singlecell/home?view=study_explorer&token=scnn1a&study=study85&studyType=human&corpus=corpus&plotBy=DisplayName&dataValue=Umap&tissueType=""&sc=df&gene=SCNN1A

Signals Percent of
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
to (Counts Per 10K) of Cells expression
to Cell
Summary of Tissue
ACE2 Expression >0
Expression of ACE2 In Individual Cell Populations
What genes have a similar expression profile in this study?

1 Tissue , 12 Cell Populations , 7.1K Cells

Among the cells selected from Goblet
NasalEpithelium this study, ACE2 is highly expressed in: 4017 7.64
1
Nasalepithelium: Club
Goblet 2

Signals Percent
Rows per page: 5 of
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
to (Counts Per 10K) of Cells expression
to Cell
Tissue >0
ACE2 Expression of ACE2 In Individual Cell Populations
NasalEpithelium
Goblet Expression1of ACE2
Tissue Across
, 12 Cell Selected
Populations , 7.1KCell
CellsPopulations
1463 7.59
2
1 Tissue , 12 Cell Populations , 7.1K Cells
Ciliated 2

Dimensionality Reduction: UMAP Color Cells By: Annotated Cell Type (From Study)
Signals Percent5 of
Rows per page:
Signals
Strength Expression in Individual Cells Number cells with
Tissue Cell Strength
https://preview.nferx.com/singlecell/home?view=study_explorer&token=ace2&study=study85&studyType=human&corpus=corpus&plotBy=DisplayName&dataValue=Umap&tissueType=""&sc=df&gene=ACE2
to (Counts Per 10K) of Cells expression
to Cell
Tissue >0

Ciliated Expression of ACE2 Across Selected Cell Populations

NasalEpithelium 1513 7.27
2 1 Tissue , 12 Cell Populations , 7.1K Cells
 keratinocytes Expression in tongue keratinocytes
Signals Percent of
Signals
Strength Number cells with
Tissue Cell Strength Expression: ln(1 + CP10K)
to of Cells expression
21/05/2020 to Cell Single Cell
Tissue >0
Expression of Ace2 in Individual Cell Populations
ENAC-⍺
18 Tissues, 148 Cell Populations, 100.6K Cells
tongue keratinocytes 3406 57.6

keratinocytes

Signals Rows per page:of

Percent 5
Signals
Strength Number cells with
Tissue Cell Strength Expression: ln(1 + CP10K)
to of Cells expression
to Cell
Tissue >0
Expression of Scnn1a Across Selected Cell Populations
ACE2
18 Tissues, 148 Cell Populations, 100.6K Cells
tongue keratinocytes 3406 41.54

Dimensionality Reduction: UMAP Color Cells By: Tissue

 cells, Connecting tubule cells, Epithelial progenitor cells
Signals Percent of
Signals
Strength Number cells with
Tissue Cell Strength Expression: ln(1 + CP10K)
21/05/2020 to Single Cell of Cells expression
to Cell
Tissue >0
Summary of SCNN1A Expression
Expression of SCNN1A in Individual Cell Populations
What genes have a similar expression profile in this study?

Principal 1 Tissue, 33 Cell Populations, 40.3K Cells

kidney the cells selected from this study, SCNN1A is highly expressed in:
Among 88 57.95
cells
kidney : Type B intercalated cells, Principal cells, Type A intercalated
connect tubule cells
proximal
cells, Connecting tubule cells, Epithelial progenitor cells

Signals
Signals Rows per page:of
Percent
Percent of
5
Signals
Signals
Strength
Strength Number
Number cells
cells with
with
Tissue
Tissue Cell
Cell Strength
Strength Expression:
Expression: ln(1
ln(1 ++ CP10K)
CP10K)
to
to of
of Cells
Cells expression
expression
to
to Cell
Cell
21/05/2020 Tissue
Tissue Single Cell >> 00
Expression ofof
Expression SCNN1A Across
SCNN1A SelectedCell
in Individual CellPopulations
Populations
Summary of ACE2 Expression
What genes have a similarConnecting
expression
Proximal
1 Tissue, 33 Cell
profile in this study? 1 Tissue, 33 Cell Populations,
Populations, 40.3K
40.3K Cells
Cells
ENAC-⍺ kidney
kidney
Among the cells
Dimensionality selectedUMAP
tubule cells
tubule
1
cells
from this study, ACE2 is not appreciably expressed
157
65 46.5
12.31

proximal Reduction:
tubule cells Color Cells By: Annotated Cell Type (From Study)

Signals Percent
Rows per page:of 5
Proximal Signals
Strength Number cells with
kidney
Tissue tubule
Cellcells Strength Expression:Single
ln(1 +Cell
CP10K) 151 6.62
21/05/2020 to SCNN1A 2
Expression Cell Colored By Annotated ofCell
CellsType (From Study
expressionShow L
to Cell
Summary of Tissue
ACE2 Expression >0
Expression of SCNN1A Across Selected Cell Populations
What genes have a similar expression profile in this study?
https://pre-staging.nferx.com/dv/201912/singlecell/home?view=study_explorer&token=scnn1a&study=study10&studyType=human&corpus=corpus&plotBy=studyAnnotation&dataValue=Umap&tissueType=""&sc=df&gene=

Among
kidney the cells selected from
kidney
Proximal
Proximal
thiscells
tubule Expression of ACE2CellinPopulations,
1 Tissue, 33
Individual40.3K
study, ACE2 is not appreciably expressed CellCells
Populations 65
27497 12.31
2.77
tubule cells
1
Dimensionality Reduction: UMAP
1 Tissue, 33 Cell Populations, 40.3K Cells
Color Cells By: Annotated Cell Type (From Study)

21/05/2020 princi Proximal Single Cell

kidney tubule cells 151 6.62
Summary of ACE2 SCNN1A
Expression
2 Expression Cell Colored By Annotated Cell Type (From Study
Show L
Signals Percent
Rows per page:of 5
What genes have a similar expression profile in this study?
Signals
Strength Number cells with
Tissue Cell Strength Expression: ln(1 + CP10K)
to Expression of ACE2 in Individual Cell Populations of Cells expression
https://pre-staging.nferx.com/dv/201912/singlecell/home?view=study_explorer&token=scnn1a&study=study10&studyType=human&corpus=corpus&plotBy=studyAnnotation&dataValue=Umap&tissueType=""&sc=df&gene=
https://pre-staging.nferx.com/dv/201912/singlecell/home?view=study_explorer&token=scnn1a&study=study10&studyType=human&corpus=corpus&plotBy=studyAnnotation&dataValue=Umap&tissueType=""&sc=df&gene=
Among the cells selected from this study, ACE2 to Cell
is not appreciably expressed
Tissue Proximal
>0
kidney
tubule cells
1 Tissue, 33 Cell Populations, 40.3K Cells 27497 2.77

Principal
connec
kidney 88 0
cells

Signals Percent of
Signals
Strength Number Rows per cells with 5
page:
Tissue Cell Strength Expression: ln(1 + CP10K)
to Expression of ACE2 in Individual Cell Populations
to Cell
of Cells Rows expression
per page: 5

Tissue >0
1 Tissue, 33 Cell Populations, 40.3K Cells
https://pre-staging.nferx.com/dv/201912/singlecell/home?view=study_explorer&token=scnn1a&study=study10&studyType=human&corpus=corpus&plotBy=studyAnnotation&dataValue=Umap&tissueType=""&sc=df&gene=

Connecting Expression of ACE2 Across Selected Cell Populations

ACE2 kidney
tubule cells
1 Tissue, 33 Cell Populations, 40.3K Cells
157 0.64

Signals Percent of
Signals
Strength Number cells with
Tissue
Dimensionality Reduction: UMAP Cell Strength Expression:Color
ln(1 + CP10K)
Cells By: Annotated Cell Type (From Study)
to of Cells Rows per
expression
page: 5
to Cell
Tissue >0

kidney
ACE2 Expression of ACE2 Across Selected
ProximalExpression CellCell Populations
Colored By Annotated Cell Type (From Study
27497 8.46
Show L
tubule cells
1 Tissue, 33 Cell Populations, 40.3K Cells
https://pre-staging.nferx.com/dv/201912/singlecell/home?view=study_explorer&token=ace2&study=study10&studyType=human&corpus=corpus&plotBy=studyAnnotation&dataValue=Umap&tissueType=""&sc=df&gene=AC
 1 Tissue, 51 Cell Populations, 110.1K Cells
Among the cells selected from this study, ACE2 is not appreciably expressed
Expression in colon enterocytes
enterocytes

Signals Percent of
Signals
Strength Number cells with
Tissue Cell Strength Expression: ln(1 + CP10K)
to of Cells expression
to Cell
Tissue >0

ENAC-⍺ Expression of ACE2 in Individual Cell Populations

colon Enterocytes 1 Tissue, 51 Cell Populations, 110.1K Cells 1997 35.85

enterocytes

Signals Immature Percent of

colon Enterocytes Signals 4401 14.79
Strength Number cells with
Tissue Cell
1 Strength Expression: ln(1 + CP10K)
to of Cells expression
to Cell
Tissue >0

Immature
colon Enterocytes 4447 23.39
ACE2 colon Enterocytes
2
1997 10.52