Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses
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Abstract
The new coronavirus (SARS-CoV-2) outbreak from December 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by SARS-CoV-2 to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, especially in the lung. SARS-CoV-2 may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted "CellPhoneDB" analysis to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.
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ACE2 expression has been reported for many tissues/organs including the lung, brain, kidney, small intestine, colon, and heart.
“ACE2 expression has been reported for many tissues/organs including the lung (ie, lung type II alveolar cells/AT2, bronchial epithelial cells), brain, kidney, small intestine, colon, and heart.”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [9]
The Results section’s ACE2 expression atlas (page unavailable) reports expression in lung AT2 cells, kidney proximal tubules, ileum enterocytes, and colon colonocytes, supporting those parts of the sentence. It does not report ACE2 expression in the brain, heart, or bronchial epithelial cells. (LLM, conf=0.89)
Experimental — accuracy not yet measuredTMPRSS2 is also required for SARS-CoV and Middle Eastern respiratory syndrome coronavirus viral entry.
“TMPRSS2 is also required for SARS-CoV and Middle Eastern respiratory syndrome coronavirus viral entry.”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [9]
The Introduction says TMPRSS2 is involved in priming SARS-CoV-2 for entry, not that it is required for SARS-CoV or MERS-CoV entry. The Results identify DPP4 as a MERS-CoV receptor, but do not address TMPRSS2's role in entry by either virus. Searches for TMPRSS2 with SARS-CoV and MERS-CoV found no passage establishing the claim. (LLM, conf=0.75)
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On the whereabouts of SARS-CoV-2 in the human body: A systematic review
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Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2
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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): a Systemic Infection
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Viral persistence, reactivation, and mechanisms of long COVID
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COVID-19, Myocarditis and Pericarditis
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Expression of SARS-CoV-2 Entry Molecules ACE2 and TMPRSS2 in the Gut of Patients With IBD
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Single-cell RNA sequencing reveals SARS-CoV-2 infection dynamics in lungs of African green monkeys
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COVID‐19 is an emergent disease of aging
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Persistent SARS-CoV-2 infection: significance and implications
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COVID‐19 and comorbidities: A role for dipeptidyl peptidase 4 ( DPP4 ) in disease severity?
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Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine
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COVID‐19 and non‐alcoholic fatty liver disease: Two intersecting pandemics
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Sex differences in SARS-CoV-2 infection rates and the potential link to prostate cancer
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Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell
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A compendium answering 150 questions on COVID‐19 and SARS‐CoV‐2
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COVID-19 and Alzheimer’s disease: how one crisis worsens the other
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COVID-19, MERS and SARS with Concomitant Liver Injury—Systematic Review of the Existing Literature
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- Authors
- Qi, F., Qian, S., Zhang, S., & Zhang, Z.
- Affiliations
- Shenzhen Third People’s Hospital (CN)
- Shanghai Medical College of Fudan University (CN)
- Southern University of Science and Technology (CN)
- Corresponding author
- Zhang, Shuye
- Zhang, Zheng
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 526
- Issue
- 1
- Pages
- 135-140
- ISSN
- 0006-291X (ISSN-L)
- PMC
- PMC7156119
- OpenAlex
- W3011994656
- Cited by
- 905
- References
- 40
- Citations by year
- 2026: 5 · 2025: 28 · 2024: 64 · 2023: 124 · 2022: 155 · 2021: 236 · 2020: 291
- FWCI
- 26.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, ACE2, coronavirus receptor, co-receptors, ANPEP, dipeptidyl peptidase IV, glutamyl aminopeptidase, proteolytic enzymes, intercellular communication, macrophages, chemokine signaling, phagocytosis, human tissue, cell types, single-cell transcriptomics, CellPhoneDB
- MeSH terms
- Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Humans, Peptidyl-Dipeptidase A, Macrophages, Organ Specificity, Peptide Hydrolases, Pneumonia, Viral, Receptors, Virus, Sequence Analysis, RNA, Coronavirus, Coronavirus Infections, Pandemics, Single-Cell Analysis
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