The protein expression profile of ACE2 in human tissues

Abstract

The international spread of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) poses a global challenge on both healthcare and society. A multitude of research efforts worldwide aim at characterizing the cellular factors involved in viral transmission in order to reveal therapeutic targets. For a full understanding of the susceptibility for SARS-CoV-2 infection, the cell type-specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is Angiotensin I converting enzyme 2 (ACE2), and its expression has been reported in various human organs, in some cases with inconsistent or contradictory results. Here, we aim to verify a reliable expression profile of ACE2 in all major human tissues and cell types. Based on stringently validated immunohistochemical analysis and highthroughput mRNA sequencing from several datasets, we found that ACE2 expression is mainly localized to microvilli of the intestinal tract and renal proximal tubules, gallbladder epithelium, testicular Sertoli cells and Leydig cells, glandular cells of seminal vesicle and cardiomyocytes. The expression in several other previously reported locations, including alveolar type II (AT2) cells, could not be confirmed. Furthermore, ACE2 expression was absent in the AT2 lung carcinoma cell line A549, often used as a model for viral replication studies. Our analysis suggests that the expression of ACE2 in the human respiratory system appears to be limited, and the expression of the receptor in lung or respiratory epithelia on the protein level is yet to be confirmed. This raises questions regarding the role of ACE2 for infection of human lungs and highlights the need to further explore the route of transmission during SARS-CoV-2 infection.

A single-cell RNA expression map of human coronavirus entry factors

“…We detected little to no expression of ACE2 and/or TMPRSS2 in the remaining tissues and cell types ( Figure 4B), including type 1 (AT1) and type 2 (AT2) alveolar cells of the lung. This latter observation is at odds with earlier reports (Table S1), but in line with a recent study using a wide array of techniques to monitor ACE2 expression within the lung, including transcriptomics, proteomics and immunostaining (Hikmet et al, 2020). Cardiomyocytes (from the heart)…”

“…However, these observations have been challenged by more recent studies. For instance, Hikmet et al could not confirm ACE2 expression in AT2 cells, neither through re-analysis of 3 different lung scRNA-seq datasets, nor by immunohistochemistry (Hikmet et al, 2020). Ziegler et al analyzed a different lung scRNA-seq dataset and found only a very small fraction (>1%) of AT2 cells expressing both ACE2 and TMPRSS2 transcripts (Ziegler et al, 2020).…”

Gene expression and in situ protein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue

“…The FANTOM5 CAGE data provides an additional and complementary approach to quantifying gene expression since a given gene’s shared promoter can yield multiple transcripts at different expression levels, as well as being partially independent of any given transcript’s half-life in the cell. In general, the promoter activity of ACE2 in airway-related tissues is low or absent; only a single sample originating from an adult lung yields a normalized CAGE promoter expression level above one transcript per million, while expression was observed in gut cells, consistent with known patterns of ACE2 expression[57]. Consistent with the microarray data, CD147 promoter activity is elevated relative to ACE2 across airway-related cells and tissues, although the relatively low CTSL (cathepsin L1) promoter activity is incongruent with modest levels of gene expression.…”

Cell-intrinsic differences between human airway epithelial cells from children and adults

“…It has been reported that SARS-CoV-2 uses ACE2 as a receptor and the TMPRSS2 protease for S priming, although cathepsin L activity may also have a role (Hoffmann et al, 2020). While ACE2 and TMPRSS2 transcripts are found in adult nasal and airway goblet and ciliated cells (Bertram et al, 2012;Sungnak et al, 2020), protein expression of ACE2 in particular seems to be low overall in airway epithelium and restricted to rare cells (Aguiar et al, 2020;Hikmet et al, 2020). Moreover, it is unclear whether these findings extend to paediatric nasal or airway epithelia.…”