{"doi":"10.1053/j.gastro.2020.09.042","title":"Angiotensin-converting Enzyme 2–containing Small Extracellular Vesicles and Exomeres Bind the Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein","abstract":"There is an increasing appreciation for the role of secreted extracellular vesicles (EVs) and nonvesicular nanoparticles in both physiologic and pathophysiologic conditions. Small EVs (sEVs) are 40- to 200-nm lipid-bilayer enclosed membrane vesicles, whereas exomeres are small (<50 nm), nonmembranous, extracellular nanoparticles.1Jeppesen D.K. et al.Cell. 2019; 177: 428-445Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar,2Zhang Q. et al.Cell Rep. 2019; 27: 940-954Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar The coronavirus disease 2019 (COVID-19) pandemic is caused by the recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).3Zhou P. Yang X.L. Wang X.G. et al.Nature. 2020; 579: 270-273Crossref PubMed Scopus (14613) Google Scholar For infection, SARS-CoV-2 must bind to the host cell receptor angiotensin-converting enzyme 2 (ACE2) to gain entry.4Hoffmann M. Kleine-Weber H. et al.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (13672) Google Scholar ACE2 is also the critical receptor used by SARS-CoV-1, responsible for the 2002–2004 SARS epidemic. Middle East respiratory syndrome (MERS) is a highly lethal respiratory disease initiated by binding of MERS-CoV to its entry receptor dipeptidyl peptidase 4 (DPP4).5Raj V.S. Mou H. et al.Nature. 2013; 495: 251-254Crossref PubMed Scopus (1588) Google Scholar ACE2 and DPP4 are highly expressed in gastrointestinal tissues, and a significant number of COVID-19, SARS, and MERS patients present with gastrointestinal symptoms.6Ding S. Liang T.J. Gastroenterology. 2020; 159: 53-61Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar,7Zang R. Gomez Castro M.F. et al.Sci Immunol. 2020; 5: eabc3582Crossref PubMed Scopus (705) Google Scholar The ectodomain of ACE2 can be released by the activity of tumor necrosis factor-α converting enzyme (TACE) and the transmembrane serine protease 2 (TMPRSS2).4Hoffmann M. Kleine-Weber H. et al.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (13672) Google Scholar The S1 subunit of the spike (S) protein of SARS-CoV-2 is primed by TMPRSS2 or TMPRSS4 for cell entry4Hoffmann M. Kleine-Weber H. et al.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (13672) Google Scholar,7Zang R. Gomez Castro M.F. et al.Sci Immunol. 2020; 5: eabc3582Crossref PubMed Scopus (705) Google Scholar, and TMPRSS2 can also prime the S protein of MERS-CoV. It has been demonstrated that human recombinant soluble ACE2, but not mouse ACE2, can inhibit SARS-CoV-2 infection,8Monteil V. et al.Cell. 2020; 181: 905-913Abstract Full Text Full Text PDF PubMed Scopus (1617) Google Scholar raising the possibility that extracellular ACE2 carried by sEVs or extracellular nanoparticles may act as a decoy to bind the virus. Here, we explore the hypothesis that sEVs and exomeres containing ACE2 can bind SARS-CoV-2. Detailed methods are available in the Supplementary Methods. Colorectal cancer cell lines LIM1215 and DiFi express high levels of ACE2, whereas Caco-2 express much less, and ACE2 was undetectable in DKO-1 (Figure 1A). After high-resolution density gradient purification,1Jeppesen D.K. et al.Cell. 2019; 177: 428-445Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar ACE2 was found to be secreted in LIM1215 and DiFi sEVs, whereas DPP4 was enriched in sEVs from LIM1215, DiFi, and DKO-1 cells (Figure 1A and Supplementary Figure 1B). The proteases TACE, TMPRSS2, and TMPRSS4 were all expressed by LIM1215, DiFi, and DKO-1 cells and secreted in sEVs (Figure 1A and Supplementary Figure 1A). To investigate further, we fractionated extracellular samples into sEV, nonvesicular, and exomere fractions.1Jeppesen D.K. et al.Cell. 2019; 177: 428-445Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar,2Zhang Q. et al.Cell Rep. 2019; 27: 940-954Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar Although cells and sEVs contain","journal":"Gastroenterology","year":2020,"id":61607,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":56,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":325626,"name":"Dennis K. Jeppesen","orcid":"0000-0002-7480-8083","position":1,"is_corresponding":false},{"id":327444,"name":"James N. Higginbotham","orcid":null,"position":2,"is_corresponding":false},{"id":86852,"name":"Jeffrey L. Franklin","orcid":"0000-0002-7111-4449","position":3,"is_corresponding":false},{"id":106531,"name":"James E. Crowe","orcid":"0000-0002-0049-1079","position":4,"is_corresponding":false},{"id":86857,"name":"Robert J. Coffey","orcid":"0000-0002-2180-3844","position":5,"is_corresponding":false},{"id":325625,"name":"Qin Zhang","orcid":"0000-0002-8379-7259","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-18T21:09:47.114172Z","pmid":"33022277","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}