Infect Dis Poverty. 2020 Apr 28;9(1):45. doi: 10.1186/s40249-020-00662-x.
Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues.Abstract BACKGROUND:
Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19),
uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to
invade human cells. Thus, ACE2 is the key to understanding the mechanism
of SARS-CoV-2
infection. This study is to investigate the ACE2 expression in various
human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection.METHODS:
We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student's t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson's correlation test.
RESULTS:
ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively.
We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student's t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson's correlation test.
RESULTS:
ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively.
CONCLUSIONS: Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.
KEYWORDS:
Angiotensin-converting enzyme 2; COVID-19; Gene expression; Immune signatures; SARS-CoV-2; SARS-CoV-2 cell receptor; SARS-CoV-2 pandemic
BACKGROUND
CONCLUSIONS:
Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.
Angiotensin-converting enzyme 2; COVID-19; Gene expression; Immune signatures; SARS-CoV-2; SARS-CoV-2 cell receptor; SARS-CoV-2 pandemic
BACKGROUND
The
outbreak of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) is rapidly spreading across the world and have caused a
global health emergency [1].
Patients infected with SARS-CoV-2 have mainly displayed
pneumonia-associated symptoms, including fever, cough, shortness of
breath, sputum production, and myalgia or fatigue [2, 3],
indicating that SARS-CoV-2 primarily infects the respiratory tract and
causes acute respiratory disease. However, SARS-CoV-2 infection may
result in symptoms of diseases associated with other tissues, such as
digestive (diarrhea, poor appetite, nausea, and vomiting), nervous
(confusion and headache), and cardiovascular (palmus, chest distress,
and cardiac injury) systems [2, 3].
In addition, some studies have indicated that person-to-person
transmission of SARS-CoV-2 can occur by routes outside of the
respiratory tract [4].
A study of 99 patients infected with SARS-CoV-2 showed that females
were less susceptible to infection than males, and older males with
comorbidities were more likely to be infected with SARS-CoV-2 [3].
Like SARS-related coronavirus (SARS-CoV) [5], SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as a host cell receptor [6,7,8]. A recent study uncovered that ACE2-expressing lung cells were more abundant in Asian males [9], potentially explaining the elevated susceptibility of males to SARS-CoV-2 infection. Nevertheless, the findings from that study are not sufficiently convincing due to a small number of samples being analyzed.
In this study, we analyzed the expression of ACE2 in various normal human tissues using the datasets from the Genotype-Tissue Expression (GTEx) project [10] and The Cancer Genome Atlas (TCGA) program (https://portal.gdc.cancer.gov/). We compared ACE2 expression levels across 31 human tissues, between males and females, and between younger and older persons in these individual tissues. Furthermore, we analyzed the correlations between ACE2 expression levels and immune signature enrichment levels in individual tissues.
Like SARS-related coronavirus (SARS-CoV) [5], SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as a host cell receptor [6,7,8]. A recent study uncovered that ACE2-expressing lung cells were more abundant in Asian males [9], potentially explaining the elevated susceptibility of males to SARS-CoV-2 infection. Nevertheless, the findings from that study are not sufficiently convincing due to a small number of samples being analyzed.
In this study, we analyzed the expression of ACE2 in various normal human tissues using the datasets from the Genotype-Tissue Expression (GTEx) project [10] and The Cancer Genome Atlas (TCGA) program (https://portal.gdc.cancer.gov/). We compared ACE2 expression levels across 31 human tissues, between males and females, and between younger and older persons in these individual tissues. Furthermore, we analyzed the correlations between ACE2 expression levels and immune signature enrichment levels in individual tissues.
Methods
Datasets
We
downloaded the GTEx RNA-Seq gene expression profiling datasets (RSEM
normalized) for 31 human normal tissues from the UCSC Xena project (https://xenabrowser.net/datapages/).
We downloaded the TCGA RNA-Seq gene expression profiling datasets (RSEM
normalized) for 12 human normal tissues from the Genomic Data Commons
Data Portal (https://portal.gdc.cancer.gov/). All gene expression values were added to 0.001 and then log2-transformed before analysis.
Evaluation of the immune signature enrichment levels in tissue
We
defined the enrichment level of an immune signature in tissue as the
mean expression level of marker genes of the immune signature in the
tissue. We analyzed four immune signatures, including CD8+ T cells,
interferon response, B cells, and natural killer (NK) cells. The CD8+ T
cell marker genes included CD2, CD247, CD28, CD3D, CD3E, CD3G, CD8A, ICAM1, ITGAL, ITGB2, PTPRC, and THY1 [11]. The interferon response marker genes included IFIT1, IFIT2, IFIT3, IRF7, ISG20, MX1, MX2, RSAD2, TNFSF10, GPR146, SELP, and AHR [12]. The B cell marker genes included BACH2, BANK1, BLK, BTLA, CD79A, CD79B, FCRL1, FCRL3, HVCN1, and RALGPS2 [12]. The NK cell marker genes included KLRC1 and KLRF1 [12].
Statistical analysis
We used Pearson’s correlation test to calculate the correlations between ACE2 expression levels and immune signature enrichment levels in individual tissues. We used a Student’s t test (two-sided) to compare ACE2
expression levels between males and females, between younger (ages
≤ 49 years) and older (ages > 49 years) persons, and between Asian
and non-Asian races in individual tissues. The adjusted P value estimated by the Benjamini and Hochberg method [13] was used to adjust for multiple tests.
Results
ACE2 expression in various human tissues
Among the 31 GTEx human tissues, the small intestine, testis, kidneys, heart, thyroid, and adipose tissue had the highest ACE2 expression levels, while blood, spleen, bone marrow, brain, blood vessels, and muscle had the lowest ACE2 expression levels (Fig. 1a). In the lungs, colon, liver, bladder, and adrenal gland, ACE2 showed medium expression levels (Fig. 1a). These results suggest that ACE2 is expressed in a wide variety of human tissues in addition to the lungs.CONCLUSIONS:
Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.
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