A comprehensive investigation of the mRNA and protein level of ACE2, the putative receptor of SARS-CoV-2, in human tissues and blood cells

Abstract

The outbreak of pneumonia caused by SARS-CoV-2 posed a great threat to global human health, which urgently requires us to understand comprehensively the mechanism of SARS-CoV-2 infection. Angiotensin-converting enzyme 2 (ACE2) was identified as a functional receptor for SARS-CoV-2, distribution of which may indicate the risk of different human organs vulnerable to SARS-CoV-2 infection. Previous studies investigating the distribution of ACE2 mRNA in human tissues only involved a limited size of the samples and a lack of determination for ACE2 protein. Given the heterogeneity among humans, the datasets covering more tissues with a larger size of samples should be analyzed. Indeed, ACE2 is a membrane and secreted protein, while the expression of ACE2 in blood and common blood cells remains unknown. Herein, the proteomic data in HIPED and the antibody-based immunochemistry result in HPA were collected to analyze the distribution of ACE2 protein in human tissues. The bulk RNA-seq profiles from three separate public datasets including HPA tissue Atlas, GTEx, and FANTOM5 CAGE were also obtained to determine the expression of ACE2 in human tissues. Moreover, the abundance of ACE2 in human blood and blood cells was determined by analyzing the data in the PeptideAtlas and the HPA Blood Atlas. We found that the mRNA expression cannot reflect the abundance of ACE2 factor due to the strong differences between mRNA and protein quantities of ACE2 within and across tissues. Our results suggested that ACE2 protein is mainly expressed in the small intestine, kidney, gallbladder, and testis, while the abundance of which in brain-associated tissues and blood common cells is low. HIPED revealed enrichment of ACE2 protein in the placenta and ovary despite a low mRNA level. Further, human secretome shows that the average concentration of ACE2 protein in the plasma of males is higher than those in females. Our research will be beneficial for understanding the transmission routes and sex-based differences in susceptibility of SARS-CoV-2 infection.

Histopathology of Third Trimester Placenta from SARS-CoV-2-Positive Women

“…In contrast, no ACE2 expression was detected in villous stroma, Hofbauer cells, or endothelial cells [14]. ACE2 protein is enriched per unit volume in the placenta and ovary, compared to other tissues, despite a low mRNA level detected in the two tissues [15]. The studies offer a potential mechanism for maternal-fetal transmission.…”

Potential Effect of COVID-19 on Maternal and Infant Outcome: Lesson From SARS

“…There were few studies that collected vaginal secretion (1/80) or infant blood (12/80); all tested negative for SARS-CoV-2 (5). Further, as revealed by HPA Tissue Atlas, vaginal secretion expresses virtually no ACE2 (62), implying that SARS-CoV-2 may not infect the tissue. Together, the risk of SARS-CoV-2 transmission by vaginal delivery seems low, although more definitive evidence is required.…”

“…However, another study revealed that SARS-CoV-2 invasion of the placenta in a woman with COVID-19 in the second trimester through molecular and immunohistochemical assays and electron microscopy ( 61 ). Moreover, the public antibody-protein profiles resident in Human Protein Atlas (HPA) revealed enrichment of the SARS-CoV-2 receptor ACE2 in the placenta and ovary ( 62 ). Collectively, the possibility of SARS-CoV-2 infection acquired from the uterus cannot be excluded, highlighting the potential for severe morbidity among pregnant women with COVID-19.…”

ACE2: The Major Cell Entry Receptor for SARS-CoV-2

“…Furthermore, the analysis of ACE2 mRNA and protein expression in experimental models, and evaluation of three different databases have demonstrated that small intestine, testis, kidney, heart muscle, colon, and thyroid gland are the overlapping tissues with the highest level of ACE2 expression, with no expression detected in blood cells [20,26]. These data explain why people affected by COVID-19 experience gastrointestinal problems and kidney dysfunction [27,28].…”

“…Due to the wide spectrum of symptoms occurring in people affected by COVID-19, efforts have been made to study ACE2 tissue expression in both mRNA and protein levels, identifying the organs more susceptible to this infection. Surprisingly, the analysis of ACE2 expression in experimental models and in human transcriptome by using different databases revealed that it is very low in the lung, mainly limited to a small fraction of type II alveolar epithelial cells [ 20 – 22 ]. Since most people present respiratory difficulties in response to SARS-CoV-2 infection, these findings were explained by the fact that the release of inflammatory cytokines, such as interferons (IFNs) caused by SARS-CoV-2, can increase the expression ACE2 and potentiate the infection [ 23 , 24 ].…”