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However, there is concern that the virus might mutate and thereby increase its transmissibility and thus pandemic potential. The pandemic SARS-CoV-2 depends on a highly cleavable furin motif at the S1\/S2 site of the viral spike (S) protein for efficient lung cell entry, transmission, and pathogenicity. Here, by employing pseudotyped particles, we investigated whether augmented cleavage at the S1\/S2 site also increases MERS-CoV entry into Calu-3 human lung cells. We report that polymorphism T746K at the S1\/S2 cleavage site or optimization of the furin motif increases S protein cleavage but not lung cell entry. These findings suggest that, unlike what has been reported for SARS-CoV-2, a highly cleavable S1\/S2 site might not augment MERS-CoV infectivity for human lung cells.<\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>The highly cleavable furin motif in the spike protein is required for robust lung cell entry, transmission, and pathogenicity of SARS-CoV-2. In contrast, it is unknown whether optimization of the furin motif in the spike protein of the pre-pandemic MERS-CoV increases lung cell entry and allows for robust human\u2013human transmission. The present study indicates that this might not be the case. Thus, neither a naturally occurring polymorphism that increased MERS-CoV spike protein cleavage nor artificial optimization of the cleavage site allowed for increased spike-protein-driven entry into Calu-3 human lung cells.<\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/jvi.01305-24","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T13:00:43Z","timestamp":1730206843000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Acquisition of a multibasic cleavage site does not increase MERS-CoV entry into Calu-3 human lung cells"],"prefix":"10.1128","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4603-7696","authenticated-orcid":false,"given":"Markus","family":"Hoffmann","sequence":"first","affiliation":[{"name":"Infection Biology Unit, German Primate Center- Leibniz Institute for Primate Research, G\u00f6ttingen, Germany"},{"name":"Faculty of Biology and Psychology, University G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Kleine-Weber","sequence":"additional","affiliation":[{"name":"Infection Biology Unit, German Primate Center- Leibniz Institute for Primate Research, G\u00f6ttingen, Germany"},{"name":"Faculty of Biology and Psychology, University G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luise","family":"Graichen","sequence":"additional","affiliation":[{"name":"Infection Biology Unit, German Primate Center- Leibniz Institute for Primate Research, G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inga","family":"Nehlmeier","sequence":"additional","affiliation":[{"name":"Infection Biology Unit, German Primate Center- Leibniz Institute for Primate Research, G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Kempf","sequence":"additional","affiliation":[{"name":"Infection Biology Unit, German Primate Center- Leibniz Institute for Primate Research, G\u00f6ttingen, Germany"},{"name":"Faculty of Biology and Psychology, University G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna-Sophie","family":"Moldenhauer","sequence":"additional","affiliation":[{"name":"Infection Biology Unit, German Primate Center- Leibniz Institute for Primate Research, G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Braun","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullah M.","family":"Assiri","sequence":"additional","affiliation":[{"name":"Preventive Health, Ministry of Health, Riyadh, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7052-2360","authenticated-orcid":true,"given":"Frank","family":"Kirchhoff","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7665-0040","authenticated-orcid":true,"given":"Daniel","family":"Sauter","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany"},{"name":"Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khaled R.","family":"Alkharsah","sequence":"additional","affiliation":[{"name":"Department of Microbiology, College of Medicine, Imam Abdulrahman Bin Faisal University (IAU), Dammam, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6086-9136","authenticated-orcid":true,"given":"Stefan","family":"P\u00f6hlmann","sequence":"additional","affiliation":[{"name":"Infection Biology Unit, German Primate Center- Leibniz Institute for Primate Research, G\u00f6ttingen, Germany"},{"name":"Faculty of Biology and Psychology, University G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60454-8"},{"key":"e_1_3_3_3_2","unstructured":"WHO. 2022. 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