{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T20:16:27Z","timestamp":1783800987260,"version":"3.55.0"},"reference-count":45,"publisher":"National Academy of Sciences","issue":"38","license":[{"start":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T00:00:00Z","timestamp":1661990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM130386"],"award-info":[{"award-number":["GM130386"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI07245"],"award-info":[{"award-number":["AI07245"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI163019"],"award-info":[{"award-number":["AI163019"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,9,20]]},"abstract":"<jats:p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry starts with membrane attachment and ends with spike (S) protein\u2013catalyzed membrane fusion depending on two cleavage steps, namely, one usually by furin in producing cells and the second by TMPRSS2 on target cells. Endosomal cathepsins can carry out both. Using real-time three-dimensional single-virion tracking, we show that fusion and genome penetration require virion exposure to an acidic milieu of pH 6.2 to 6.8, even when furin and TMPRSS2 cleavages have occurred. We detect the sequential steps of S1-fragment dissociation, fusion, and content release from the cell surface in TMPRRS2-overexpressing cells only when exposed to acidic pH. We define a key role of an acidic environment for successful infection, found in endosomal compartments and at the surface of TMPRSS2-expressing cells in the acidic milieu of the nasal cavity.<\/jats:p>","DOI":"10.1073\/pnas.2209514119","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T13:58:42Z","timestamp":1662040722000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":96,"title":["SARS-CoV-2 requires acidic pH to infect cells"],"prefix":"10.1073","volume":"119","author":[{"given":"Alex J. B.","family":"Kreutzberger","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwesha","family":"Sanyal","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Saminathan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5648-3190","authenticated-orcid":false,"given":"Louis-Marie","family":"Bloyet","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University in Saint Louis, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer","family":"Stumpf","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University in Saint Louis, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8198-0976","authenticated-orcid":false,"given":"Zhuoming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University in Saint Louis, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Ojha","sequence":"additional","affiliation":[{"name":"Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, 00290 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7346-2554","authenticated-orcid":false,"given":"Markku T.","family":"Patjas","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Phoniatrics - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, 00290 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Geneid","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Phoniatrics - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, 00290 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Scanavachi","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A.","family":"Doyle","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Virginia, Charlottesville, VA 22903"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliott","family":"Somerville","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Bango Da Cunha","family":"Correia","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Di Caprio","sequence":"additional","affiliation":[{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanna","family":"Toppila-Salmi","sequence":"additional","affiliation":[{"name":"Department of Allergy, University of Helsinki and Helsinki University Hospital, Helsinki, 00290 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antti","family":"M\u00e4kitie","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology and Phoniatrics - Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, 00290 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9388-5703","authenticated-orcid":false,"given":"Volker","family":"Kiessling","sequence":"additional","affiliation":[{"name":"Center for Membrane and Cell Physiology, University of Virginia, Charlottesville, VA 22903"},{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22903"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2270-6824","authenticated-orcid":false,"given":"Olli","family":"Vapalahti","sequence":"additional","affiliation":[{"name":"Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, 00290 Finland"},{"name":"Department of Veterinary Biosciences, University of Helsinki, Helsinki, 00290 Finland"},{"name":"Virology and Immunology, Helsinki University Hospital Diagnostic Center, Helsinki,  00290 Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1564-8590","authenticated-orcid":false,"given":"Sean P. J.","family":"Whelan","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, Washington University in Saint Louis, St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3585-559X","authenticated-orcid":false,"given":"Giuseppe","family":"Balistreri","sequence":"additional","affiliation":[{"name":"Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, 00290 Finland"},{"name":"Department of Veterinary Biosciences, University of Helsinki, Helsinki, 00290 Finland"},{"name":"The Queensland Brain Institute, University of Queensland, Brisbane, 4072 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Kirchhausen","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115"},{"name":"Program in Cellular and Molecular Medicine, Boston Children\u2019s Hospital, Boston, MA 02115"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,9]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.02.052"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2507"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18319-6"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2762"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2003138117"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00418-x"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03237-4"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abc3582"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00975-21"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15562-9"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-021-00908-w"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202000786"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.06.021"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1257998"},{"key":"e_1_3_4_15_2","first-page":"359","article-title":"The morphology of vesicular stomatitis virus, (Indiana C) derived from chick embryos or cultures of BHK21\/13 cells","volume":"44","author":"Bradish C. J.","year":"1966","unstructured":"C. J. Bradish, J. B. Kirkham, The morphology of vesicular stomatitis virus, (Indiana C) derived from chick embryos or cultures of BHK21\/13 cells. Microbiology 44, 359\u2013371 (1966).","journal-title":"Microbiology"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001127"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a016857"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3266"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.127.4.915"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2006.04.002"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2007837117"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2012197117"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809524106"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.3390\/v12101174"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18781-2"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2273.1999.00223.x"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjoto.2013.04.015"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02232-10"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2011.02.020"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1407087111"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0807771105"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00333"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.04389"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1618883114"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04474-x"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2021.2023329"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00619-9"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI106164"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf4896"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e16-03-0164"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004355"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.05.047"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2021.05.015"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e14-06-1146"},{"key":"e_1_3_4_45_2","unstructured":"V. Kirchheim TrackBrowser_LabView. GitHub. https:\/\/github.com\/VolkerKirchheim\/TrackBrowser_LabView.git. Deposited 23 May 2022."}],"updated-by":[{"DOI":"10.1073\/pnas.2417740121","type":"expression_of_concern","label":"Expression of concern","source":"publisher","updated":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T00:00:00Z","timestamp":1728259200000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2209514119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T13:58:57Z","timestamp":1662040737000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2209514119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9]]},"references-count":45,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2022,9,20]]}},"alternative-id":["10.1073\/pnas.2209514119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2209514119","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.742304931.793598415","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.06.09.495472","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9]]},"assertion":[{"value":"2022-06-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2209514119"}}