Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis
Open accessAbstract
Severe acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS‐CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin‐converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS‐CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS‐CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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The SARS-CoV-2 Spike protein mediates binding of coronaviruses to ACE2 on the surface of various cell types including epithelial cells of the pulmonary alveolus.
“The S protein mediates binding of coronaviruses to angiotensin converting enzyme 2 (ACE2) on the surface of various cell types including epithelial cells of the pulmonary alveolus (4–6).”
From An <i>Alphavirus</i> -derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates (2020) · cites this paper as [4]
Bulk data on ACE2 distribution cannot indicate cell type-specific expression.
“Previous studies have investigated the ACE2 mRNA and protein expression in various tissues by bulk samples17,18, however, the distribution of ACE2 through bulk data could not indicate the cell type-specific expression of ACE2.”
From High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa (2020) · cites this paper as [18]
ACE2 is expressed in the brain and heart.
“Since the receptor for SARS‐Cov‐2, angiotensin‐converting enzyme 2 (ACE2) is expressed in the brain and heart (Hamming et al, 2004), it is possible that viral‐mediated entry of these cells induces VIS and localised inflammation leading to tissue dysfunction.”
From The struggle of a good friend getting old: cellular senescence in viral responses and therapy (2021) · cites this paper as Hamming et al, 2004
ACE2 protein in human brain is predominantly or exclusively expressed in vasculature, specifically within pericytes.
“Multiple immunostaining studies reveal that ACE2 protein in the human brain is predominantly or exclusively expressed in vasculature (and specifically expressed within pericytes) (52, 53, 70), and many neurological symptoms associated with CoV-2 infection like stroke or altered consciousness are consistent with an underlying vasculopathy (71-76).”
From Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia (2020) · cites this paper as [52]
Re-analysis of 10 deeply sequenced SMART-Seq2-based scSeq datasets from different regions of the nervous system demonstrated that Ace2 and Tmprss2 expression is almost completely absent from neurons.
“re-analysis of 10 deeply sequenced SMART-Seq2-based scSeq datasets from different regions of the nervous system demonstrated that Ace2 and Tmprss2 expression is almost completely absent from neurons, consistent with prior immunostaining results (52, 53) (Figure S10).”
From Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia (2020) · cites this paper as [52]
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- Authors
- Hamming, I., Timens, W., Bulthuis, M., Lely, A., Navis, G., & van Goor, H.
- Affiliations
- University Medical Center Groningen (NL)
- Corresponding author
- Timens, W
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2004-05-07
- Volume
- 203
- Issue
- 2
- Pages
- 631-637
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- PMC
- PMC7167720
- OpenAlex
- W2167384912
- Cited by
- 5,676
- References
- 22
- Citations by year
- 2026: 51 · 2025: 131 · 2024: 305 · 2023: 487 · 2022: 905 · 2021: 1589 · 2020: 1907 · 2019: 8 · 2018: 8 · 2017: 10 · 2016: 16 · 2015: 13 · 2014: 19 · 2013: 13 · 2012: 19
- FWCI
- 23.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Takeda Oncology
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- angiotensin-converting enzyme 2, SARS-CoV, SARS pathogenesis, tissue distribution, viral receptor, alveolar epithelial cells, vascular endothelial cells, smooth muscle cells, human organs
- MeSH terms
- Arteries, Epithelial Cells, Female, Humans, Immunohistochemistry, Intestine, Small, Peptidyl-Dipeptidase A, Male, Middle Aged, Muscle, Smooth, Muscle, Smooth, Vascular, Pulmonary Alveoli, Receptors, Virus, Skin, Veins, Viral Proteins, Enterocytes, Severe Acute Respiratory Syndrome, Severe acute respiratory syndrome-related coronavirus
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