{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T14:57:28Z","timestamp":1774969048028,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T00:00:00Z","timestamp":1639699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["LP: 2018-03233"],"award-info":[{"award-number":["LP: 2018-03233"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"name":"IMM strategic grant","award":["SU-COVID (2020-2021)"],"award-info":[{"award-number":["SU-COVID (2020-2021)"]}]},{"name":"Swedish Heart Lung Foundation","award":["(KG: 20200776)"],"award-info":[{"award-number":["(KG: 20200776)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Background: The SARS-CoV-2 spike protein mediates attachment of the virus to the host cell receptor and fusion between the virus and the cell membrane. The S1 subunit of the spike glycoprotein (S1 protein) contains the angiotensin converting enzyme 2 (ACE2) receptor binding domain. The SARS-CoV-2 variants of concern contain mutations in the S1 subunit. The spike protein is the primary target of neutralizing antibodies generated following infection, and constitutes the viral component of mRNA-based COVID-19 vaccines. Methods: Therefore, in this work we assessed the effect of exposure (24 h) to 10 nM SARS-CoV-2 recombinant S1 protein on physiologically relevant human bronchial (bro) and alveolar (alv) lung mucosa models cultured at air\u2013liquid interface (ALI) (n = 6 per exposure condition). Corresponding sham exposed samples served as a control. The bro-ALI model was developed using primary bronchial epithelial cells and the alv-ALI model using representative type II pneumocytes (NCI-H441). Results: Exposure to S1 protein induced the surface expression of ACE2, toll like receptor (TLR) 2, and TLR4 in both bro-ALI and alv-ALI models. Transcript expression analysis identified 117 (bro-ALI) and 97 (alv-ALI) differentially regulated genes (p \u2264 0.01). Pathway analysis revealed enrichment of canonical pathways such as interferon (IFN) signaling, influenza, coronavirus, and anti-viral response in the bro-ALI. Secreted levels of interleukin (IL) 4 and IL12 were significantly (p &lt; 0.05) increased, whereas IL6 decreased in the bro-ALI. In the case of alv-ALI, enriched terms involving p53, APRIL (a proliferation-inducing ligand) tight junction, integrin kinase, and IL1 signaling were identified. These terms are associated with lung fibrosis. Further, significantly (p &lt; 0.05) increased levels of secreted pro-inflammatory cytokines IFN\u03b3, IL1\ua7b5, IL2, IL4, IL6, IL8, IL10, IL13, and tumor necrosis factor alpha were detected in alv-ALI, whereas IL12 was decreased. Altered levels of these cytokines are also associated with lung fibrotic response. Conclusions: In conclusion, we observed a typical anti-viral response in the bronchial model and a pro-fibrotic response in the alveolar model. The bro-ALI and alv-ALI models may serve as an easy and robust platform for assessing the pathogenicity of SARS-CoV-2 variants of concern at different lung regions.<\/jats:p>","DOI":"10.3390\/v13122537","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T02:40:32Z","timestamp":1639968032000},"page":"2537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Differential Effect of SARS-CoV-2 Spike Glycoprotein 1 on Human Bronchial and Alveolar Lung Mucosa Models: Implications for Pathogenicity"],"prefix":"10.3390","volume":"13","author":[{"given":"Mizanur","family":"Rahman","sequence":"first","affiliation":[{"name":"Unit of Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17 177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Irmler","sequence":"additional","affiliation":[{"name":"Institute of Experimental Genetics, Helmholtz Zentrum M\u00fcnchen GmbH, 85764 Neuherberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2403-4083","authenticated-orcid":false,"given":"Sandeep","family":"Keshavan","sequence":"additional","affiliation":[{"name":"Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, 1700 Fribourg, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5564-1994","authenticated-orcid":false,"given":"Micol","family":"Introna","sequence":"additional","affiliation":[{"name":"Unit of Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17 177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1038-7160","authenticated-orcid":false,"given":"Johannes","family":"Beckers","sequence":"additional","affiliation":[{"name":"Institute of Experimental Genetics, Helmholtz Zentrum M\u00fcnchen GmbH, 85764 Neuherberg, Germany"},{"name":"German Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany"},{"name":"Chair of Experimental Genetics, Technical University of Munich, 85354 Freising, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lena","family":"Palmberg","sequence":"additional","affiliation":[{"name":"Unit of Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17 177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8759-9567","authenticated-orcid":false,"given":"Gunnar","family":"Johanson","sequence":"additional","affiliation":[{"name":"Unit of Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17 177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8531-8154","authenticated-orcid":false,"given":"Koustav","family":"Ganguly","sequence":"additional","affiliation":[{"name":"Unit of Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17 177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swapna","family":"Upadhyay","sequence":"additional","affiliation":[{"name":"Unit of Integrative Toxicology, Institute of Environmental Medicine, Karolinska Institutet, 17 177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41579-021-00573-0","article-title":"SARS-CoV-2 variants, spike mutations and immune escape","volume":"19","author":"Harvey","year":"2021","journal-title":"Nat. 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