Figures and data in ACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities

Figures
Tables

1 figure and 3 tables

Figures

Figure 1

Download asset Open asset

Angiotensin-converting enzyme 2 (ACE2), the proposed receptor of SARS-CoV-2, is expressed in the respiratory airways at low levels (blue) compared to the intestine, kidney, heart, and pancreas.

Low levels are also observed in the liver. In nasal and bronchial tissues, ACE2 is mainly expressed by ciliated, club, and goblet cells. It is also found in type-2 pneumocytes of alveoli and in endothelial cells of pulmonary capillaries. In comorbidities associated with a severity and poor prognosis of COVID-19, ACE2 levels are increased in the lungs of COPD and smokers and in the heart of patients with cardiovascular diseases (CVD). In contrast, patients with hypertension exhibit decreased levels of ACE2 in the kidney. In T2D patients, ACE2 is decreased in the pancreas and the vascular system but increased in the lungs. Current evidence supports a possible role of co-receptors or attachment factors, such as neuropilins, heparan sulfate, and sialic acids. The low detection of ACE2 in respiratory tissues also led to the speculation of a role of alternative receptors, such as CD147 and GRP78.

Tables

Table 1

Measure of the dissociation constant (Kd) of ACE2 bound to immobilized SARS-CoV or SARS-CoV-2 S proteins by surface plasmon resonance (SPR) or biolayer interferometry binding (BLI) approaches.

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
Wrapp et al., 2020	1–615 aa		1–1208 aa	SPR	14.7 nM
Wang et al., 2020a	19–615 aa	306–527 aa		SPR	408.7 nM
Wang et al., 2020a	19–615 aa		319–541 aa	SPR	133.3 nM
Lan et al., 2020	19–615 aa	306–527 aa		SPR	31.6 nM
Lan et al., 2020	19–615 aa		319–541 aa	SPR	4.7 nM
Walls et al., 2020	1–614 aa	306–575 aa		BLI	1.2 nM
Walls et al., 2020	1–614 aa		328–533 aa	BLI	5 nM
Wrapp et al., 2020	1–615 aa	306–577 aa		BLI	13.7 nM
Wrapp et al., 2020	1–615 aa		319–591 aa	BLI	34.6 nM

Table 2

mRNA levels of ACE2 found in the lungs, small intestine, kidney, and heart muscle reported in the Human Protein Atlas (HPA) consortium (Uhlén et al., 2015), the genome‐based tissue expression (GTEx) consortium (Keen and Moore, 2015).

Activity levels of the promoter of ACE2 assembled in the Fantom (FANTOM5) consortium (Yu et al., 2015). Protein-transcripts per million (pTPM). Scaled Tags Per Million (sTPM).

	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

Table 3

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).

Provider refers to the information found in the website of the company. IB: Immunoblot. IHC: Immunohistochemistry. IF: Immunofluorescence. Enhanced validation, Supportive validation, No data available, + Positive detection, +/- Weak detection, - Absence of detection.

	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