{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T06:46:04Z","timestamp":1782369964746,"version":"3.54.5"},"reference-count":55,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R21AR081520"],"award-info":[{"award-number":["5R21AR081520"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R21AI168798"],"award-info":[{"award-number":["5R21AI168798"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30AR075049"],"award-info":[{"award-number":["P30AR075049"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The primary route of SARS-CoV-2 entry is via respiratory epithelium. However, many COVID-19 patients developed dermatological lesions, and SARS-CoV-2 RNA has been detected in the patients\u2019 skin. Inflammatory skin diseases, psoriasis and atopic dermatitis (AD), significantly increased the risk of COVID-19. To evaluate the potential role of skin in SARS-CoV-2 host interactions, we utilized 3D human skin organoids (HSO) generated from human epidermal keratinocytes, as well as neonatal skin explants. HSO were treated with cytokines involved in acute and chronic skin inflammation and cytokine storm in severe COVID-19 disease: TNF-\u03b1, IL-6, IL-1\u03b2, and IFN-\u03b3, individually and in combination. HSO were also treated with Th1 (TNF-\u03b1 + IL-17) and Th2 (IL-4 + IL-13) cocktails inducing pro-psoriasis and pro-AD HSO changes, respectively. All individual cytokines, and especially their combinations, elevated the expression of ACE2 and TMPRSS2 at mRNA\/protein levels. The Th2 cocktail induced only TMPRSS2, the Th1 cocktail predominantly induced ACE2. Topically applied Spike-pseudotyped lentiviral Tomato reporter, which binds ACE2 similarly to SARS-CoV-2, successfully transduced control and cytokine-treated HSO as well as neonatal skin explants. Cytokine treatment, especially TNF-\u03b1 + IL-6 + IL-1\u03b2 + IFN-\u03b3 and the Th1 cocktail, significantly increased viral entry. Transcriptomic analysis further revealed partial overlap between gene expression signatures induced by Spike-mediated entry in inflamed HSO and those observed in lung tissue from COVID-19 patients, supporting the biological relevance of skin models. Together, these findings demonstrate that inflammation may transiently alter the permissiveness of human skin to SARS-CoV-2 entry, suggesting that the skin may represent a previously underappreciated, although likely limited, interface in viral- host interactions.<\/jats:p>","DOI":"10.3390\/ijms27125382","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:49:01Z","timestamp":1781570941000},"page":"5382","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Skin as a Potential Entry Point for SARS-CoV-2 Virus"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5801-2504","authenticated-orcid":false,"given":"Dimitri","family":"Trubetskoy","sequence":"first","affiliation":[{"name":"Department of Dermatology, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Grudzien","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9354-6824","authenticated-orcid":false,"given":"Daria","family":"Chudakova","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University, Chicago, IL 60611, USA"},{"name":"Center for Precision Genetic Technologies for Medicine, Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0556-3414","authenticated-orcid":false,"given":"Anna","family":"Klopot","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University, Chicago, IL 60611, USA"},{"name":"Division of Medical Biochemistry, Department of Biochemistry and Immunochemistry, Faculty of Medicine, Wroclaw Medical University, 50-368 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj","family":"Bhalla","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University, Chicago, IL 60611, USA"},{"name":"Skin Biology and Diseases Resource-Based Center, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5594-0599","authenticated-orcid":false,"given":"Bethany","family":"Perez White","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University, Chicago, IL 60611, USA"},{"name":"Skin Biology and Diseases Resource-Based Center, Northwestern University, Chicago, IL 60611, USA"},{"name":"Department of Dermatology, Rush Medical College, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5880-6822","authenticated-orcid":false,"given":"Irina","family":"Budunova","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Northwestern University, Chicago, IL 60611, USA"},{"name":"Skin Biology and Diseases Resource-Based Center, Northwestern University, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.molcel.2020.04.022","article-title":"A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for Infection of human lung cells","volume":"78","author":"Hoffmann","year":"2020","journal-title":"Mol. 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