CoChat
Sign Up
Cited by 498SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesSingle-cell and spatial transcriptomics

Digestive system is a potential route of COVID-19: an analysis of single-cell coexpression pattern of key proteins in viral entry process

Open access
Zhang, Hao, Kang, Zijian, Gong, Haiyi, Xu, Da, Wang, Jing, Li, Zhixiu, Li, Zifu, Cui, Xinggang +6 more·2020·Gut
DOI 10.1136/gutjnl-2020-320953PMC PMC7211082
Open this paper in CoChat — free accountOpen PDF

Abstract

Objective: Since December 2019, a newly identified coronavirus (severe acute respiratory syndrome coronavirus (SARS-CoV-2)) has caused outbreaks of pneumonia in Wuhan, China. SARS-CoV-2 enters host cells via cell receptor ACE II (ACE2) and the transmembrane serine protease 2 (TMPRSS2). In order to identify possible prime target cells of SARS-CoV-2 by comprehensive dissection of ACE2 and TMPRSS2 coexpression pattern in different cell types, five datasets with single-cell transcriptomes of lung, oesophagus, gastric mucosa, ileum and colon were analysed. Design: Five datasets were searched, separately integrated and analysed. Violin plot was used to show the distribution of differentially expressed genes for different clusters. The ACE2-expressing and TMPRRSS2-expressing cells were highlighted and dissected to characterise the composition and proportion. Results: Cell types in each dataset were identified by known markers. ACE2 and TMPRSS2 were not only coexpressed in lung AT2 cells and oesophageal upper epithelial and gland cells but also highly expressed in absorptive enterocytes from the ileum and colon. Additionally, among all the coexpressing cells in the normal digestive system and lung, the expression of ACE2 was relatively highly expressed in the ileum and colon. Conclusion: This study provides the evidence of the potential route of SARS-CoV-2 in the digestive system along with the respiratory tract based on single-cell transcriptomic analysis. This finding may have a significant impact on health policy setting regarding the prevention of SARS-CoV-2 infection. Our study also demonstrates a novel method to identify the prime cell types of a virus by the coexpression pattern analysis of single-cell sequencing data.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1136/gutjnl-2020-320953

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [17]

    The Results (Cell type-specific ACE2 and TMPRSS2 expression; page unavailable) report ACE2 expression in lung AT2 cells, small intestine, and colon. The passages found do not establish expression in the brain, kidney, heart, or bronchial epithelial cells. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 43

  1. [1]The Lancet Emerging understandings of 2019-nCoV. Lancet 2020; 395: 311. 10.1016/S0140-6736(20)30186-0 31986259 PMC7134625 · DOI
  2. [2]Zhu N, Zhang D, Wang W, et al A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382: 727– 33. 10.1056/NEJMoa2001017 31978945 PMC7092803 · DOI · Paper page
  3. [3]Chan JF-W, Yuan S, Kok K-H, et al A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020; 395: 514– 23. 10.1016/S0140-6736(20)30154-9 31986261 PMC7159286 · DOI
  4. [4]Huang C, Wang Y, Li X, et al Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497– 506. 10.1016/S0140-6736(20)30183-5 31986264 PMC7159299 · DOI · Paper page
  5. [5]Chen N, Zhou M, Dong X, et al Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395: 507– 13. 10.1016/S0140-6736(20)30211-7 32007143 PMC7135076 · DOI · Paper page
  6. [6]Wang D, Hu B, Hu C, et al Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020. 10.1001/jama.2020.1585. [Epub ahead of print: 07 Feb 2020]. PMC7042881 32031570 · DOI · Paper page
  7. [7]Li F Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol 2016; 3: 237– 61. 10.1146/annurev-virology-110615-042301 27578435 PMC5457962 · DOI · Paper page
  8. [8]Gui M, Song W, Zhou H, et al Cryo-Electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conformational state for receptor binding. Cell Res 2017; 27: 119– 29. 10.1038/cr.2016.152 28008928 PMC5223232 · DOI
  9. [9]Zhou P, Yang X-L, Wang X-G, et al A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270– 3. 10.1038/s41586-020-2012-7 32015507 PMC7095418 · DOI · Paper page
  10. [10]Xu X, Chen P, Wang J, et al Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 2020; 63: 457– 60. 10.1007/s11427-020-1637-5 32009228 PMC7089049 · DOI
  11. [12]Gallagher TM, Buchmeier MJ Coronavirus spike proteins in viral entry and pathogenesis. Virology 2001; 279: 371– 4. 10.1006/viro.2000.0757 11162792 PMC7133764 · DOI · Paper page
  12. [13]Hoffmann M, Kleine-Weber H, Schroeder S, et al SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020. 10.1016/j.cell.2020.02.052 PMC7102627 32142651 · DOI · Paper page
  13. [15]Madissoon E, Wilbrey-Clark A, Miragaia RJ, et al scRNA-Seq assessment of the human lung, spleen, and esophagus tissue stability after cold preservation. Genome Biol 2019; 21: 1. 10.1186/s13059-019-1906-x 31892341 PMC6937944 · DOI
  14. [16]Zhang P, Yang M, Zhang Y, et al Dissecting the single-cell transcriptome network underlying gastric premalignant lesions and early gastric cancer. Cell Rep 2019; 27: 1934– 47. 10.1016/j.celrep.2019.04.052 31067475 · DOI
  15. [17]Martin JC, Chang C, Boschetti G, et al Single-Cell analysis of Crohn's disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 2019; 178: 1493– 508. 10.1016/j.cell.2019.08.008 31474370 PMC7060942 · DOI
  16. [18]Smillie CS, Biton M, Ordovas-Montanes J, et al Intra- and Inter-cellular rewiring of the human colon during ulcerative colitis. Cell 2019; 178: 714– 30. 10.1016/j.cell.2019.06.029 31348891 PMC6662628 · DOI
  17. [19]Stuart T, Butler A, Hoffman P, et al Comprehensive integration of single-cell data. Cell 2019; 177: 1888– 902. 10.1016/j.cell.2019.05.031 31178118 PMC6687398 · DOI · Paper page
  18. [20]Welch JD, Kozareva V, Ferreira A, et al Single-Cell multi-omic integration compares and contrasts features of brain cell identity. Cell 2019; 177: 1873– 87. 10.1016/j.cell.2019.05.006 31178122 PMC6716797 · DOI · Paper page
  19. [21]GTEx Consortium Human genomics. The Genotype-Tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 2015; 348: 648– 60. 10.1126/science.1262110 25954001 PMC4547484 · DOI · Paper page
  20. [22]Uhlen M, Fagerberg L, Hallstrom BM, et al Tissue-Based map of the human proteome. Science 2015; 347: 1260419 10.1126/science.1260419 25613900 · DOI · Paper page
  21. [23]Perlman S, Netland J Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 2009; 7: 439– 50. 10.1038/nrmicro2147 19430490 PMC2830095 · DOI
  22. [24]Zou X, Chen K, Zou J, et al Single-Cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 2020. 10.1007/s11684-020-0754-0 PMC7088738 32170560 · DOI · Paper page
  23. [25]Chai X, Hu L, Zhang Y, et al Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. BioRxiv 2020.
  24. [26]Peiris JSM, Chu CM, Cheng VCC, et al Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 2003; 361: 1767– 72. 10.1016/S0140-6736(03)13412-5 12781535 PMC7112410 · DOI · Paper page
  25. [27]Powers JH, Bacci ED, Guerrero ML, et al Reliability, validity, and responsiveness of influenza patient-reported outcome (FLU-PRO©) scores in Influenza-Positive patients. Value Health 2018; 21: 210– 8. 10.1016/j.jval.2017.04.014 29477403 PMC5831548 · DOI
  26. [28]To KF, Tong JHM, Chan PKS, et al Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases. J Pathol 2004; 202: 157– 63. 10.1002/path.1510 14743497 PMC7167900 · DOI
  27. [29]Li F, Li W, Farzan M Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 2005; 309: 1864– 8. 10.1126/science.1116480 16166518 · DOI
  28. [30]Song W, Gui M, Wang X, et al Cryo-Em structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog 2018; 14: e1007236. 10.1371/journal.ppat.1007236 30102747 PMC6107290 · DOI
  29. [31]Yang X-L, Hu B, Wang B, et al Isolation and characterization of a novel bat coronavirus closely related to the direct progenitor of severe acute respiratory syndrome coronavirus. J Virol 2015; 90: 3253– 6. 10.1128/JVI.02582-15 26719272 PMC4810638 · DOI
  30. [33]Hu B, Zeng L-P, Yang X-L, et al Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathog 2017; 13: e1006698. 10.1371/journal.ppat.1006698 29190287 PMC5708621 · DOI
  31. [35]Shirato K, Kawase M, Matsuyama S Wild-Type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry. Virology 2018; 517: 9– 15. 10.1016/j.virol.2017.11.012 29217279 PMC7112029 · DOI
  32. [36]Heurich A, Hofmann-Winkler H, Gierer S, et al Tmprss2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 2014; 88: 1293– 307. 10.1128/JVI.02202-13 24227843 PMC3911672 · DOI
  33. [37]Zhou Y, Vedantham P, Lu K, et al Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res 2015; 116: 76– 84. 10.1016/j.antiviral.2015.01.011 25666761 PMC4774534 · DOI
  34. [38]Meng T, Cao H, Zhang H, et al The insert sequence in SARS-CoV-2 enhances spike protein cleavage by TMPRSS. bioRxiv 2020.
  35. [39]Qian Z, Travanty EA, Oko L, et al Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus. Am J Respir Cell Mol Biol 2013; 48: 742– 8. 10.1165/rcmb.2012-0339OC 23418343 PMC3727876 · DOI
  36. [40]Nabhan AN, Brownfield DG, Harbury PB, et al Single-Cell Wnt signaling niches maintain stemness of alveolar type 2 cells. Science 2018; 359: 1118– 23. 10.1126/science.aam6603 29420258 PMC5997265 · DOI
  37. [41]Que J, Okubo T, Goldenring JR, et al Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development 2007; 134: 2521– 31. 10.1242/dev.003855 17522155 PMC3625644 · DOI
  38. [42]Zhang Y, Jiang M, Kim E, et al Development and stem cells of the esophagus. Semin Cell Dev Biol 2017; 66: 25– 35. 10.1016/j.semcdb.2016.12.008 28007661 PMC5474349 · DOI
  39. [43]Jiang M, Li H, Zhang Y, et al Transitional basal cells at the squamous-columnar junction generate Barrett's oesophagus. Nature 2017; 550: 529– 33. 10.1038/nature24269 29019984 PMC5831195 · DOI
  40. [44]Haber AL, Biton M, Rogel N, et al A single-cell survey of the small intestinal epithelium. Nature 2017; 551: 333– 9. 10.1038/nature24489 29144463 PMC6022292 · DOI · Paper page
  41. [45]Crawford SE, Ramani S, Tate JE, et al Rotavirus infection. Nat Rev Dis Primers 2017; 3: 17083. 10.1038/nrdp.2017.83 29119972 PMC5858916 · DOI
  42. [47]Desmarets LMB, Theuns S, Roukaerts IDM, et al Role of sialic acids in feline enteric coronavirus infections. J Gen Virol 2014; 95: 1911– 8. 10.1099/vir.0.064717-0 24876305 · DOI
  43. [48]Holshue ML, DeBolt C, Lindquist S, et al First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; 382: 929– 36. 10.1056/NEJMoa2001191 32004427 PMC7092802 · DOI · Paper page

Cited by

Sorted by citations

Authors
Zhang, H., Kang, Z., Gong, H., Xu, D., Wang, J., Li, Z., Li, Z., Cui, X., Xiao, J., Zhan, J., Meng, T., Zhou, W., Liu, J., & Xu, H.
Affiliations
  • Second Military Medical University (CN)
  • Translational Research Institute (AU)
  • Griffith University (AU)
  • Tongji University (CN)
  • Center for Life Sciences (CN)
Corresponding author
Xu, Huji
ORCID
Venue
Gut
Publisher
BMJ
Published
2020-04-02
Volume
69
Issue
6
Pages
1010-1018
ISSN
  • 0017-5749 (ISSN-L)
  • 1468-3288
DOI
10.1136/gutjnl-2020-320953
PMC
PMC7211082
OpenAlex
W3014703367
Cited by
498
References
6
Citations by year
2026: 8 · 2025: 21 · 2024: 39 · 2023: 39 · 2022: 89 · 2021: 167 · 2020: 135
FWCI
14.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Gut (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • QUT ePrints (Queensland University of Technology) (submittedVersion, cc-by-nc)
  • HighWire Press Open Archive (submittedVersion)
  • Griffith Research Online (submittedVersion, cc-by-nc)
Funders
  • the China Ministry of Science and Technology (2018AAA0100300)
  • National Natural Science Foundation of China (31821003, 81702659)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Keywords
SARS-CoV-2, COVID-19 pandemic, ACE2, TMPRSS2, viral entry, digestive system, enterocytes, ileum, colon, esophagus, lung, single-cell transcriptomics, cell types, infection route

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review