{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:56:16Z","timestamp":1792068976427,"version":"4.4.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T00:00:00Z","timestamp":1636329600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>\n                    The SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The data available about COVID-19 during pregnancy have demonstrated placental infection; however, the mechanisms associated with intrauterine transmission of SARS-CoV-2 is still debated. Intriguingly, while canonical SARS-CoV-2 cell entry mediators are expressed at low levels in placental cells, the receptors for viruses that cause congenital infections such as the cytomegalovirus and Zika virus are highly expressed in these cells. Here we analyzed the transcriptional profile (microarray and single-cell RNA-Seq) of proteins potentially interacting with coronaviruses to identify non- canonical mediators of SARS-CoV-2 infection and replication in the placenta. Despite low levels of the canonical cell entry mediators\n                    <jats:italic>ACE2<\/jats:italic>\n                    and\n                    <jats:italic>TMPRSS2<\/jats:italic>\n                    , we show that cells of the syncytiotrophoblast, villous cytotrophoblast, and extravillous trophoblast co-express high levels of the potential non-canonical cell-entry mediators\n                    <jats:italic>DPP4<\/jats:italic>\n                    and\n                    <jats:italic>CTSL<\/jats:italic>\n                    . We also found changes in the expression of\n                    <jats:italic>DAAM1<\/jats:italic>\n                    and\n                    <jats:italic>PAICS<\/jats:italic>\n                    genes during pregnancy, which are translated into proteins also predicted to interact with coronaviruses proteins. These results provide new insight into the interaction between SARS-CoV-2 and host proteins that may act as non-canonical routes for SARS-CoV-2 infection and replication in the placenta cells.\n                  <\/jats:p>","DOI":"10.3389\/fmolb.2021.614728","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T03:10:17Z","timestamp":1636341017000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Prediction of Non-canonical Routes for SARS-CoV-2 Infection in Human Placenta Cells"],"prefix":"10.3389","volume":"8","author":[{"given":"Fl\u00e1via Bessi","family":"Constantino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah Santiloni","family":"Cury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia Regina","family":"Nogueira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robson Francisco","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Antonio","family":"Justulin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"783","DOI":"10.3389\/fcell.2020.00783","article-title":"Single-Cell RNA-Seq Identifies Cell Subsets in Human Placenta that Highly Expresses Factors Driving Pathogenesis of SARS-CoV-2","volume":"8","author":"Ashary","year":"2020","journal-title":"Front. Cel Dev. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"eaaw6284","DOI":"10.1126\/sciadv.aaw6284","article-title":"Congenital Zika Syndrome Is Associated with Maternal Protein Malnutrition","volume":"6","author":"Barbeito-Andr\u00e9s","year":"2020","journal-title":"Sci. Adv."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.placenta.2020.05.012","article-title":"Factors Preventing Materno-Fetal Transmission of SARS-CoV-2","volume":"97","author":"Celik","year":"2020","journal-title":"Placenta"},{"key":"B4","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/S0140-6736(20)30360-3","article-title":"Clinical Characteristics and Intrauterine Vertical Transmission Potential of COVID-19 Infection in Nine Pregnant Women: A Retrospective Review of Medical Records","volume":"395","author":"Chen","year":"2020","journal-title":"The Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1101\/2020.06.12.148411","article-title":"Prediction of Non-Canonical Routes for SARS-CoV-2 Infection in Human Placenta Cells","author":"Constantino","year":"2020"},{"key":"B6","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S1473-3099(20)30120-1","article-title":"An Interactive Web-Based Dashboard to Track COVID-19 in Real Time","volume":"20","author":"Dong","year":"","journal-title":"Lancet Infect. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1846","DOI":"10.1001\/jama.2020.4621","article-title":"Possible Vertical Transmission of SARS-CoV-2 from an Infected Mother to Her Newborn","volume":"323","author":"Dong","year":"","journal-title":"JAMA"},{"key":"B8","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1186\/s12985-014-0228-6","article-title":"Identification of Putative Interactions between Swine and Human Influenza A Virus Nucleoprotein and Human Host Proteins","volume":"11","author":"Generous","year":"2014","journal-title":"Virol. J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/ng.3259","article-title":"Understanding Multicellular Function and Disease with Human Tissue-Specific Networks","volume":"47","author":"Greene","year":"2015","journal-title":"Nat. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1038\/s41467-020-14586-5","article-title":"Temporal Dynamics of Protein Complex Formation and Dissociation during Human Cytomegalovirus Infection","volume":"11","author":"Hashimoto","year":"2020","journal-title":"Nat. Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3075","DOI":"10.1096\/fj.13-247049","article-title":"Daam1 Is a Regulator of Filopodia Formation and Phagocytic Uptake of Borrelia Burgdorferi by Primary Human Macrophages","volume":"28","author":"Hoffmann","year":"2014","journal-title":"FASEB j."},{"key":"B12","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"crossref","DOI":"10.1172\/JCI139569","article-title":"SARS-CoV-2 Infection of the Placenta.","author":"Hosier","year":"2020"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1001\/jama.2020.4868","article-title":"Can SARS-CoV-2 Infection Be Acquired In Utero?: More Definitive Evidence Is Needed","volume":"323","author":"Kimberlin","year":"2020","journal-title":"JAMA"},{"key":"B15","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1111\/j.1749-6632.2001.tb03798.x","article-title":"The Mechanisms of Placental Viral Infection","volume":"943","author":"Koi","year":"2001","journal-title":"Ann. N.Y Acad. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1016\/j.cell.2019.08.005","article-title":"A Structure-Informed Atlas of Human-Virus Interactions","volume":"178","author":"Lasso","year":"2019","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.antiviral.2017.11.001","article-title":"Nsp3 of Coronaviruses: Structures and Functions of a Large Multi-Domain Protein","volume":"149","author":"Lei","year":"2018","journal-title":"Antiviral Res."},{"key":"B18","doi-asserted-by":"crossref","DOI":"10.1007\/b138038","volume-title":"Coronavirus Replication and Reverse Genetics","author":"Enjuanes","year":"2005"},{"key":"B19","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1038\/s41564-020-0688-y","article-title":"Functional Assessment of Cell Entry and Receptor Usage for SARS-CoV-2 and Other Lineage B Betacoronaviruses","volume":"5","author":"Letko","year":"2020","journal-title":"Nat. Microbiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"101160","DOI":"10.1016\/j.isci.2020.101160","article-title":"The MERS-CoV Receptor DPP4 as a Candidate Binding Target of the SARS-CoV-2 Spike","volume":"23","author":"Li","year":"2020","journal-title":"iScience"},{"key":"B21","doi-asserted-by":"publisher","first-page":"107587","DOI":"10.1016\/j.pharmthera.2020.107587","article-title":"Cathepsin L-Selective Inhibitors: A Potentially Promising Treatment for COVID-19 Patients","volume":"213","author":"Liu","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"B22","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/j.medj.2021.04.016","article-title":"Maternal Respiratory SARS-CoV-2 Infection in Pregnancy Is Associated with a Robust Inflammatory Response at the Maternal-Fetal Interface","volume":"2","author":"Lu-Culligan","year":"2021","journal-title":"Med"},{"key":"B23","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1177\/1933719108322425","article-title":"Profiling Gene Expression in Human Placentae of Different Gestational Ages: An OPRU* Network and UW SCOR Study","volume":"15","author":"Mikheev","year":"2008","journal-title":"Reprod. Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1038\/s41467-020-15562-9","article-title":"Characterization of Spike Glycoprotein of SARS-CoV-2 on Virus Entry and its Immune Cross-Reactivity with SARS-CoV","volume":"11","author":"Ou","year":"2020","journal-title":"Nat. Commun."},{"key":"B25","doi-asserted-by":"publisher","first-page":"100145","DOI":"10.1016\/j.ajogmf.2020.100145","article-title":"Vertical Transmission of Coronavirus Disease 2019: Severe Acute Respiratory Syndrome Coronavirus 2 RNA on the Fetal Side of the Placenta in Pregnancies with Coronavirus Disease 2019-positive Mothers and Neonates at Birth","volume":"2","author":"Patan\u00e8","year":"2020","journal-title":"Am. J. Obstet. Gynecol. MFM"},{"key":"B26","doi-asserted-by":"publisher","first-page":"100133","DOI":"10.1016\/j.ajogmf.2020.100133","article-title":"Detection of Severe Acute Respiratory Syndrome Coronavirus 2 in Placental and Fetal Membrane Samples","volume":"2","author":"Penfield","year":"2020","journal-title":"Am. J. Obstet. Gynecol. MFM"},{"key":"B27","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1146\/annurev-virology-092917-043236","article-title":"Congenital Viral Infection: Traversing the Uterine-Placental Interface","volume":"5","author":"Pereira","year":"2018","journal-title":"Annu. Rev. Virol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/s41586-018-0446-y","article-title":"The Emergence of Zika Virus and its New Clinical Syndromes","volume":"560","author":"Pierson","year":"2018","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e58716","DOI":"10.7554\/eLife.58716","article-title":"Does the Human Placenta Express the Canonical Cell Entry Mediators for SARS-CoV-2?","volume":"9","author":"Pique-Regi","year":"2020","journal-title":"eLife"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1080\/14767058.2020.1765334","article-title":"Pregnancy Affected by SARS-CoV-2 Infection: A Flash Report from Michigan","author":"Qadri","year":"2020","journal-title":"J. Maternal-Fetal Neonatal Med."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1101\/2020.06.08.20110437","article-title":"SARS-CoV-2 Placental Infection and Inflammation Leading to Fetal Distress and Neonatal Multi-Organ Failure in an Asymptomatic Woman","author":"Schoenmakers","year":"2020","journal-title":"medRxiv"},{"key":"B32","doi-asserted-by":"publisher","first-page":"194","DOI":"10.3390\/v12020194","article-title":"Potential Maternal and Infant Outcombes from Coronavirus 2019-nCoV (SARS-CoV-2) Infecting Pregnant Women: Lessons from SARS, MERS, and Other Human Coronavirus Infections","volume":"12","author":"Schwartz","year":"2020","journal-title":"Viruses"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.3390\/v12111308","article-title":"Placental Pathology of COVID-19 with and without Fetal and Neonatal Infection: Trophoblast Necrosis and Chronic Histiocytic Intervillositis as Risk Factors for Transplacental Transmission of SARS-CoV-2","volume":"12","author":"Schwartz","year":"2020","journal-title":"Viruses"},{"key":"B34","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1093\/ajcp\/aqaa089","article-title":"Placental Pathology in COVID-19","volume":"154","author":"Shanes","year":"2020","journal-title":"Am. J. Clin. Pathol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1093\/humrep\/deaa367","article-title":"Persistence of SARS-CoV-2 in the First Trimester Placenta Leading to Transplacental Transmission and Fetal Demise from an Asymptomatic Mother","volume":"36","author":"Shende","year":"2021","journal-title":"Hum. Reprod."},{"key":"B36","doi-asserted-by":"publisher","first-page":"11876","DOI":"10.1073\/pnas.0505577102","article-title":"Inhibitors of Cathepsin L Prevent Severe Acute Respiratory Syndrome Coronavirus Entry","volume":"102","author":"Simmons","year":"2005","journal-title":"Proc. Natl. Acad. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"108175","DOI":"10.1016\/j.celrep.2020.108175","article-title":"A Single-Cell RNA Expression Map of Human Coronavirus Entry Factors","volume":"32","author":"Singh","year":"2020","journal-title":"Cel Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/s41591-020-0868-6","article-title":"SARS-CoV-2 Entry Factors Are Highly Expressed in Nasal Epithelial Cells Together with Innate Immune Genes","volume":"26","author":"Sungnak","year":"2020","journal-title":"Nat. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"4480","DOI":"10.1002\/jmv.26965","article-title":"Fetal and Placental Infection with SARS\u2010CoV\u20102 in Early Pregnancy","volume":"93","author":"Valdespino\u2010V\u00e1zquez","year":"2021","journal-title":"J. Med. Virol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41586-018-0698-6","article-title":"Single-Cell Reconstruction of the Early Maternal-Fetal Interface in Humans","volume":"563","author":"Vento-Tormo","year":"2018","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1038\/s41586-020-2521-4","article-title":"Factors Associated with COVID-19-related Death Using OpenSAFELY","volume":"584","author":"Williamson","year":"2020","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/s41586-020-2008-3","article-title":"A New Coronavirus Associated with Human Respiratory Disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1055\/s-0040-1712161","article-title":"Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2: A Systematic Review","volume":"37","author":"Yang","year":"2020","journal-title":"Am. J. Perinatol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1848","DOI":"10.1001\/jama.2020.4861","article-title":"Antibodies in Infants Born to Mothers with COVID-19 Pneumonia","volume":"323","author":"Zeng","year":"2020","journal-title":"JAMA"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1101\/2020.05.24.111823","article-title":"The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I","author":"Zhang","year":"2020","journal-title":"bioRxiv"},{"key":"B46","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.614728\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T03:10:19Z","timestamp":1636341019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2021.614728\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,8]]},"references-count":47,"alternative-id":["10.3389\/fmolb.2021.614728"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2021.614728","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.06.12.148411","asserted-by":"object"}]},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,8]]},"article-number":"614728"}}