{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T09:06:59Z","timestamp":1785229619407,"version":"3.55.0"},"reference-count":97,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T00:00:00Z","timestamp":1732060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","award":["197785619\u2014SFB 1021"],"award-info":[{"award-number":["197785619\u2014SFB 1021"]}]},{"name":"State of Hesse LOEWE Center CoroPan","award":["197785619\u2014SFB 1021"],"award-info":[{"award-number":["197785619\u2014SFB 1021"]}]},{"name":"Pandemienetzwerk Hessen","award":["197785619\u2014SFB 1021"],"award-info":[{"award-number":["197785619\u2014SFB 1021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The zoonotic transmission of influenza A viruses (IAVs) and coronaviruses (CoVs) may result in severe disease. Cleavage of the surface glycoproteins hemagglutinin (HA) and spike protein (S), respectively, is essential for viral infectivity. The transmembrane serine protease 2 (TMPRSS2) is crucial for cleaving IAV HAs containing monobasic cleavage sites and severe acute respiratory syndrome (SARS)-CoV-2 S in human airway cells. Here, we analysed and compared the TMPRSS2-dependency of SARS-CoV, Middle East respiratory syndrome (MERS)-CoV, the 1918 pandemic H1N1 IAV and IAV H12, H13 and H17 subtypes in human airway cells. We used the peptide-conjugated morpholino oligomer (PPMO) T-ex5 to knockdown the expression of active TMPRSS2 and determine the impact on virus activation and replication in Calu-3 cells. The activation of H1N1\/1918 and H13 relied on TMPRSS2, whereas recombinant IAVs carrying H12 or H17 were not affected by TMPRSS2 knockdown. MERS-CoV replication was strongly suppressed in T-ex5 treated cells, while SARS-CoV was less dependent on TMPRSS2. Our data underline the importance of TMPRSS2 for certain (potentially) pandemic respiratory viruses, including H1N1\/1918 and MERS-CoV, in human airways, further suggesting a promising drug target. However, our findings also highlight that IAVs and CoVs differ in TMPRSS2 dependency and that other proteases are involved in virus activation.<\/jats:p>","DOI":"10.3390\/v16111798","type":"journal-article","created":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T03:57:04Z","timestamp":1732075024000},"page":"1798","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unveiling the Role of TMPRSS2 in the Proteolytic Activation of Pandemic and Zoonotic Influenza Viruses and Coronaviruses in Human Airway Cells"],"prefix":"10.3390","volume":"16","author":[{"given":"Marie","family":"Schwerdtner","sequence":"first","affiliation":[{"name":"Institute of Virology, Philipps-University Marburg, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luna C.","family":"Schmacke","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Philipps-University Marburg, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Nave","sequence":"additional","affiliation":[{"name":"Institute of Virology, Philipps-University Marburg, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Limburg","sequence":"additional","affiliation":[{"name":"Institute of Virology, Philipps-University Marburg, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6523-4754","authenticated-orcid":false,"given":"Torsten","family":"Steinmetzer","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Philipps-University Marburg, 35037 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5446-5167","authenticated-orcid":false,"given":"David A.","family":"Stein","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong M.","family":"Moulton","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0007-8110","authenticated-orcid":false,"given":"Eva","family":"B\u00f6ttcher-Friebertsh\u00e4user","sequence":"additional","affiliation":[{"name":"Institute of Virology, Philipps-University Marburg, 35043 Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,20]]},"reference":[{"key":"ref_1","first-page":"359","article-title":"Evolution and ecology of influenza A viruses","volume":"385","author":"Yoon","year":"2014","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_2","unstructured":"WHO (2023, December 01). Influenza (Seasonal): Fact Sheet. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/influenza-(seasonal)?gclid=CjwKCAiApaarBhB7EiwAYiMwqkrgFmvbClJ5v5pvnSviACe5YD_RahWgEog8qpXvWrCstwEHMqiEtBoCI2kQAvD_BwE."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1353\/bhm.2002.0022","article-title":"Updating the accounts: Global mortality of the 1918\u20131920 \u201cSpanish\u201d influenza pandemic","volume":"76","author":"Johnson","year":"2002","journal-title":"Bull. Hist. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/B978-0-12-809633-8.21501-X","article-title":"Human Coronavirus-229E, -OC43, -NL63, and -HKU1 (Coronaviridae)","volume":"2","author":"Liu","year":"2021","journal-title":"Encycl. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0140-6736(03)13967-0","article-title":"Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome","volume":"362","author":"Kuiken","year":"2003","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.prrv.2004.07.011","article-title":"Epidemiology of severe acute respiratory syndrome (SARS): Adults and children","volume":"5","author":"Zhong","year":"2004","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1056\/NEJMoa1211721","article-title":"Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia","volume":"367","author":"Zaki","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_8","unstructured":"WHO (2024, July 17). Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Fact Sheet. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/middle-east-respiratory-syndrome-coronavirus-(mers-cov)."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1056\/NEJMoa1401505","article-title":"Evidence for camel-to-human transmission of MERS coronavirus","volume":"370","author":"Azhar","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1056\/NEJMoa1306742","article-title":"Hospital outbreak of Middle East respiratory syndrome coronavirus","volume":"369","author":"Assiri","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1056\/NEJMoa1408636","article-title":"2014 MERS-CoV outbreak in Jeddah\u2014A link to health care facilities","volume":"372","author":"Oboho","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1093\/cid\/ciu812","article-title":"An observational, laboratory-based study of outbreaks of middle East respiratory syndrome coronavirus in Jeddah and Riyadh, kingdom of Saudi Arabia, 2014","volume":"60","author":"Drosten","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nrm1076","article-title":"The structural biology of type I viral membrane fusion","volume":"4","author":"Colman","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/viro.1999.9716","article-title":"Role of hemagglutinin cleavage for the pathogenicity of influenza virus","volume":"258","author":"Steinhauer","year":"1999","journal-title":"Virology"},{"key":"ref_15","first-page":"93","article-title":"Acid-induced membrane fusion by the hemagglutinin protein and its role in influenza virus biology","volume":"385","author":"Russell","year":"2014","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5871","DOI":"10.1073\/pnas.0809524106","article-title":"Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites","volume":"106","author":"Belouzard","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"557","DOI":"10.3390\/v4040557","article-title":"Ready, set, fuse! The coronavirus spike protein and acquisition of fusion competence","volume":"4","author":"Gallagher","year":"2012","journal-title":"Viruses"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.virusres.2014.11.021","article-title":"Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis","volume":"202","author":"Millet","year":"2015","journal-title":"Virus Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7411","DOI":"10.1128\/JVI.00079-09","article-title":"Characterization of a highly conserved domain within the severe acute respiratory syndrome coronavirus spike protein S2 domain with characteristics of a viral fusion peptide","volume":"83","author":"Madu","year":"2009","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nature16988","article-title":"Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer","volume":"531","author":"Walls","year":"2016","journal-title":"Nature"},{"key":"ref_21","first-page":"3","article-title":"The hemagglutinin: A determinant of pathogenicity","volume":"385","author":"Garten","year":"2014","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9896","DOI":"10.1128\/JVI.01118-06","article-title":"Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium","volume":"80","author":"Matrosovich","year":"2006","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e00649-19","DOI":"10.1128\/JVI.00649-19","article-title":"TMPRSS2 Is the Major Activating Protease of Influenza A Virus in Primary Human Airway Cells and Influenza B Virus in Human Type II Pneumocytes","volume":"93","author":"Limburg","year":"2019","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e0090621","DOI":"10.1128\/JVI.00906-21","article-title":"Hemagglutinins of Avian Influenza Viruses Are Proteolytically Activated by TMPRSS2 in Human and Murine Airway Cells","volume":"95","author":"Bestle","year":"2021","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hatesuer, B., Bertram, S., Mehnert, N., Bahgat, M.M., Nelson, P.S., P\u00f6hlmann, S., and Schughart, K. (2013). Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003774"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4744","DOI":"10.1128\/JVI.03799-13","article-title":"TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice","volume":"88","author":"Tarnow","year":"2014","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5608","DOI":"10.1128\/JVI.03677-13","article-title":"The host protease TMPRSS2 plays a major role in in vivo replication of emerging H7N9 and seasonal influenza viruses","volume":"88","author":"Sakai","year":"2014","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s12985-020-01323-z","article-title":"H2 influenza A virus is not pathogenic in Tmprss2 knock-out mice","volume":"17","author":"Lambertz","year":"2020","journal-title":"Virol. J."},{"key":"ref_29","doi-asserted-by":"crossref","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":"ref_30","doi-asserted-by":"crossref","unstructured":"Padmanabhan, P., Desikan, R., and Dixit, N.M. (2020). Targeting TMPRSS2 and Cathepsin B\/L together may be synergistic against SARS-CoV-2 infection. PLoS Comput. Biol., 16.","DOI":"10.26434\/chemrxiv.12213125"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e202000786","DOI":"10.26508\/lsa.202000786","article-title":"TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells","volume":"3","author":"Bestle","year":"2020","journal-title":"Life Sci. Alliance"},{"key":"ref_32","doi-asserted-by":"crossref","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":"ref_33","doi-asserted-by":"crossref","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. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8887","DOI":"10.1128\/JVI.00415-08","article-title":"Cathepsin L functionally cleaves the severe acute respiratory syndrome coronavirus class I fusion protein upstream of rather than adjacent to the fusion peptide","volume":"82","author":"Bosch","year":"2008","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12658","DOI":"10.1128\/JVI.01542-10","article-title":"Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2","volume":"84","author":"Matsuyama","year":"2010","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.antiviral.2013.09.028","article-title":"Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research","volume":"100","author":"Simmons","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Burkard, C., Verheije, M.H., Wicht, O., van Kasteren, S.I., van Kuppeveld, F.J., Haagmans, B.L., Pelkmans, L., Rottier, P.J.M., Bosch, B.J., and de Haan, C.A.M. (2014). Coronavirus cell entry occurs through the endo-\/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004502"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/infdis\/jiu407","article-title":"Inhibition of proprotein convertases abrogates processing of the middle eastern respiratory syndrome coronavirus spike protein in infected cells but does not reduce viral infectivity","volume":"211","author":"Gierer","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00683-18","DOI":"10.1128\/JVI.00683-18","article-title":"Middle East Respiratory Syndrome Coronavirus Spike Protein Is Not Activated Directly by Cellular Furin during Viral Entry into Target Cells","volume":"92","author":"Matsuyama","year":"2018","journal-title":"J. Virol."},{"key":"ref_40","first-page":"e58892","article-title":"A Fluorogenic Peptide Cleavage Assay to Screen for Proteolytic Activity: Applications for coronavirus spike protein activation","volume":"143","author":"Jaimes","year":"2019","journal-title":"J. Vis. Exp."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"\u00d6rd, M., Faustova, I., and Loog, M. (2020). The sequence at Spike S1\/S2 site enables cleavage by furin and phospho-regulation in SARS-CoV2 but not in SARS-CoV1 or MERS-CoV. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-74101-0"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"12552","DOI":"10.1128\/JVI.01890-13","article-title":"Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2","volume":"87","author":"Shirato","year":"2013","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5502","DOI":"10.1128\/JVI.00128-13","article-title":"The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies","volume":"87","author":"Gierer","year":"2013","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e01815-18","DOI":"10.1128\/JVI.01815-18","article-title":"TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection","volume":"93","author":"Okamura","year":"2019","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1038\/s41467-021-21171-x","article-title":"Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide","volume":"12","author":"Li","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"6100","DOI":"10.1038\/s41467-022-33911-8","article-title":"Essential role of TMPRSS2 in SARS-CoV-2 infection in murine airways","volume":"13","author":"Kakizaki","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101303","DOI":"10.1016\/j.coviro.2023.101303","article-title":"The role of influenza-A virus and coronavirus viral glycoprotein cleavage in host adaptation","volume":"58","author":"Heindl","year":"2023","journal-title":"Curr. Opin. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6108","DOI":"10.1073\/pnas.100133697","article-title":"A DNA transfection system for generation of influenza A virus from eight plasmids","volume":"97","author":"Hoffmann","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"11388","DOI":"10.1074\/jbc.RA120.012635","article-title":"Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways","volume":"295","author":"Harbig","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.jconrel.2006.09.011","article-title":"Vectorization of morpholino oligomers by the (R-Ahx-R)4 peptide allows efficient splicing correction in the absence of endosomolytic agents","volume":"116","author":"Abes","year":"2006","journal-title":"J. Control. Release"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1021\/acsmedchemlett.0c00651","article-title":"The Basicity Makes the Difference: Improved Canavanine-Derived Inhibitors of the Proprotein Convertase Furin","volume":"12","author":"Heindl","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1128\/JVI.01294-10","article-title":"Inhibition of Influenza Virus Infection in Human Airway Cell Cultures by an Antisense Peptide-Conjugated Morpholino Oligomer Targeting the Hemagglutinin-Activating Protease TMPRSS2","volume":"85","author":"Stein","year":"2011","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Hierholzer, J.C., and Killington, R.A. (1996). Virus isolation and quantitation. Virology Methods Manual, Elsevier.","DOI":"10.1016\/B978-012465330-6\/50003-8"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ab.2013.07.043","article-title":"Synthesis and characterization of novel fluorogenic substrates of coagulation factor XIII-A","volume":"442","author":"Hardes","year":"2013","journal-title":"Anal. Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1023\/A:1024141823692","article-title":"Addition of o-aminobenzoic acid during Fmoc solid phase synthesis of a fluorogenic substrate containing 3-nitrotyrosine","volume":"9","author":"Singh","year":"2002","journal-title":"Lett. Pept. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1038\/s41589-022-01059-7","article-title":"Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation","volume":"18","author":"Fraser","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e0010224","DOI":"10.1128\/jvi.00102-24","article-title":"ACE2 acts as a novel regulator of TMPRSS2-catalyzed proteolytic activation of influenza A virus in airway cells","volume":"98","author":"Heindl","year":"2024","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"12087","DOI":"10.1128\/JVI.01427-14","article-title":"DESC1 and MSPL activate influenza A viruses and emerging coronaviruses for host cell entry","volume":"88","author":"Zmora","year":"2014","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Kishimoto, M., Uemura, K., Sanaki, T., Sato, A., Hall, W.W., Kariwa, H., Orba, Y., Sawa, H., and Sasaki, M. (2021). TMPRSS11D and TMPRSS13 Activate the SARS-CoV-2 Spike Protein. Viruses, 13.","DOI":"10.3390\/v13030384"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Laporte, M., Raeymaekers, V., van Berwaer, R., Vandeput, J., Marchand-Casas, I., Thibaut, H.-J., van Looveren, D., Martens, K., Hoffmann, M., and Maes, P. (2021). The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009500"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1128\/JVI.05300-11","article-title":"Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease","volume":"85","author":"Bertram","year":"2011","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4122","DOI":"10.1128\/JVI.02232-10","article-title":"Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response","volume":"85","author":"Glowacka","year":"2011","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Saraste, J., and Prydz, K. (2021). Assembly and Cellular Exit of Coronaviruses: Hijacking an Unconventional Secretory Pathway from the Pre-Golgi Intermediate Compartment via the Golgi Ribbon to the Extracellular Space. Cells, 10.","DOI":"10.3390\/cells10030503"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6537","DOI":"10.1128\/JVI.00094-12","article-title":"Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry","volume":"86","author":"Kawase","year":"2012","journal-title":"J. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nature02951","article-title":"Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus","volume":"431","author":"Kobasa","year":"2004","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"B\u00f6ttcher-Friebertsh\u00e4user, E., Garten, W., and Klenk, H.D. (2018). Activation of Viruses by Host Proteases, Springer International Publishing.","DOI":"10.1007\/978-3-319-75474-1"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1128\/JVI.02205-08","article-title":"Proteolytic activation of the 1918 influenza virus hemagglutinin","volume":"83","author":"Chaipan","year":"2009","journal-title":"J. Virol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e01430-19","DOI":"10.1128\/JVI.01430-19","article-title":"Hemagglutinin Cleavability, Acid Stability, and Temperature Dependence Optimize Influenza B Virus for Replication in Human Airways","volume":"94","author":"Laporte","year":"2019","journal-title":"J. Virol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/BF01309867","article-title":"Pathogenicity of influenza A\/Seal\/Mass\/1\/80 virus mutants for mammalian species","volume":"140","author":"Scheiblauer","year":"1995","journal-title":"Arch. Virol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e107821","DOI":"10.15252\/embj.2021107821","article-title":"TMPRSS2 expression dictates the entry route used by SARS-CoV-2 to infect host cells","volume":"40","author":"Koch","year":"2021","journal-title":"EMBO J."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Li, K., Markosyan, R.M., Zheng, Y.-M., Golfetto, O., Bungart, B., Li, M., Ding, S., He, Y., Liang, C., and Lee, J.C. (2013). IFITM proteins restrict viral membrane hemifusion. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003124"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3683","DOI":"10.3390\/v6093683","article-title":"IFITM proteins inhibit entry driven by the MERS-coronavirus spike protein: Evidence for cholesterol-independent mechanisms","volume":"6","author":"Wrensch","year":"2014","journal-title":"Viruses"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e01387-16","DOI":"10.1128\/JVI.01387-16","article-title":"Clinical Isolates of Human Coronavirus 229E Bypass the Endosome for Cell Entry","volume":"91","author":"Shirato","year":"2016","journal-title":"J. Virol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.virol.2017.11.012","article-title":"Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry","volume":"517","author":"Shirato","year":"2018","journal-title":"Virology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"15214","DOI":"10.1073\/pnas.1407087111","article-title":"Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein","volume":"111","author":"Millet","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4525","DOI":"10.1021\/cr010168i","article-title":"Precursor processing by kex2\/furin proteases","volume":"102","author":"Rockwell","year":"2002","journal-title":"Chem. Rev."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/2049-632X.12053","article-title":"Activation of influenza viruses by proteases from host cells and bacteria in the human airway epithelium","volume":"69","author":"Klenk","year":"2013","journal-title":"Pathog. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Galloway, S.E., Reed, M.L., Russell, C.J., and Steinhauer, D.A. (2013). Influenza HA subtypes demonstrate divergent phenotypes for cleavage activation and pH of fusion: Implications for host range and adaptation. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003151"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Hoffmann, M., Kr\u00fcger, N., Zmora, P., Wrensch, F., Herrler, G., and P\u00f6hlmann, S. (2016). The Hemagglutinin of Bat-Associated Influenza Viruses Is Activated by TMPRSS2 for pH-Dependent Entry into Bat but Not Human Cells. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152134"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1038\/s41564-019-0517-3","article-title":"Entry of the bat influenza H17N10 virus into mammalian cells is enabled by the MHC class II HLA-DR receptor","volume":"4","author":"Giotis","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"5154","DOI":"10.1128\/JVI.00124-15","article-title":"A mutant H3N2 influenza virus uses an alternative activation mechanism in TMPRSS2 knockout mice by loss of an oligosaccharide in the hemagglutinin stalk region","volume":"89","author":"Sakai","year":"2015","journal-title":"J. Virol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/0042-6822(84)90376-3","article-title":"Is virulence of H5N2 influenza viruses in chickens associated with loss of carbohydrate from the hemagglutinin?","volume":"139","author":"Kawaoka","year":"1984","journal-title":"Virology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1099\/jgv.0.001128","article-title":"Exchange of amino acids in the H1-haemagglutinin to H3 residues is required for efficient influenza A virus replication and pathology in Tmprss2 knock-out mice","volume":"99","author":"Lambertz","year":"2018","journal-title":"J. Gen. Virol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4269","DOI":"10.1073\/pnas.1116200109","article-title":"A distinct lineage of influenza A virus from bats","volume":"109","author":"Tong","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41586-019-0955-3","article-title":"MHC class II proteins mediate cross-species entry of bat influenza viruses","volume":"567","author":"Karakus","year":"2019","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1073\/pnas.1218509110","article-title":"Hemagglutinin homologue from H17N10 bat influenza virus exhibits divergent receptor-binding and pH-dependent fusion activities","volume":"110","author":"Zhu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Freidl, G.S., Binger, T., M\u00fcller, M.A., de Bruin, E., van Beek, J., Corman, V.M., Rasche, A., Drexler, J.F., Sylverken, A., and Oppong, S.K. (2015). Serological evidence of influenza A viruses in frugivorous bats from Africa. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0127035"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1128\/JVI.01635-13","article-title":"Activation of influenza A viruses by host proteases from swine airway epithelium","volume":"88","author":"Peitsch","year":"2014","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Bertram, S., Heurich, A., Lavender, H., Gierer, S., Danisch, S., Perin, P., Lucas, J.M., Nelson, P.S., P\u00f6hlmann, S., and Soilleux, E.J. (2012). Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035876"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Zmora, P., Molau-Blazejewska, P., Bertram, S., Walendy-Gnir\u00df, K., Nehlmeier, I., Hartleib, A., Moldenhauer, A.-S., Konzok, S., Dehmel, S., and Sewald, K. (2017). Non-human primate orthologues of TMPRSS2 cleave and activate the influenza virus hemagglutinin. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176597"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e126","DOI":"10.1038\/emi.2016.125","article-title":"A camel-derived MERS-CoV with a variant spike protein cleavage site and distinct fusion activation properties","volume":"5","author":"Millet","year":"2016","journal-title":"Emerg. Microbes Infect."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1073\/pnas.1718769115","article-title":"MERS coronaviruses from camels in Africa exhibit region-dependent genetic diversity","volume":"115","author":"Chu","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e01774-19","DOI":"10.1128\/JVI.01774-19","article-title":"Trypsin Treatment Unlocks Barrier for Zoonotic Bat Coronavirus Infection","volume":"94","author":"Menachery","year":"2020","journal-title":"J. Virol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1080\/22221751.2021.2023329","article-title":"SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with delta variant in TMPRSS2-expressed cells","volume":"11","author":"Zhao","year":"2021","journal-title":"Emerg. Microbes Infect."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/s41586-022-04474-x","article-title":"Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity","volume":"603","author":"Meng","year":"2022","journal-title":"Nature"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1038\/s41564-022-01143-7","article-title":"SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway","volume":"7","author":"Willett","year":"2022","journal-title":"Nat. Microbiol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Aggarwal, A., Akerman, A., Milogiannakis, V., Silva, M.R., Walker, G., Stella, A.O., Kindinger, A., Angelovich, T., Waring, E., and Amatayakul-Chantler, S. (2022). SARS-CoV-2 Omicron BA.5: Evolving tropism and evasion of potent humoral responses and resistance to clinical immunotherapeutics relative to viral variants of concern. eBioMedicine, 84.","DOI":"10.1016\/j.ebiom.2022.104270"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/11\/1798\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:35:40Z","timestamp":1760114140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/11\/1798"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,20]]},"references-count":97,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,11]]}},"alternative-id":["v16111798"],"URL":"https:\/\/doi.org\/10.3390\/v16111798","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,20]]}}}