{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:45:22Z","timestamp":1790732722718,"version":"4.1.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The role of vitamin D in Coronavirus Disease 2019 (COVID-19) outcomes remains debated, but emerging evidence suggests it may enhance recovery by strengthening immune responses. Vitamin D upregulates LL-37, an antimicrobial peptide with broad antiviral activity, including potential benefits against SARS-CoV-2. LL-37\u2019s interactions with viral proteins, however, remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated LL-37\u2019s interactions with the SARS-CoV-2 Spike glycoprotein and the accessory proteins ORF7a and ORF8 using surface plasmon resonance and negative-stain electron microscopy. These approaches were employed to assess LL-37\u2019s binding capabilities and potential impact on viral infectivity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      LL-37 bound multiple domains of the Spike protein and inhibited its interaction with the human angiotensin-converting enzyme 2 (hACE2) receptor\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Up to seven LL-37 molecules were observed surrounding Spike, forming a halo-like structure that may block receptor engagement. LL-37 also bound to ORF7a and ORF8, potentially impairing their ability to disrupt host cell processes. Notably, LL-37\u2019s interaction with ORF7a may prevent degradation of SNAP29, restoring autophagy and promoting viral clearance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>LL-37 disrupts key viral-host interactions by binding to Spike, ORF7a, and ORF8, thereby reducing SARS-CoV-2 infectivity. These findings highlight LL-37\u2019s potential as a therapeutic agent in COVID-19 and provide mechanistic insight into its antiviral actions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2025.1671738","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T05:30:03Z","timestamp":1758605403000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Vitamin D-inducible antimicrobial peptide LL-37 binds SARS-CoV-2 Spike and accessory proteins ORF7a and ORF8"],"prefix":"10.3389","volume":"15","author":[{"given":"Annika","family":"Roth","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"L\u00fctke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"M\u00f6rgelin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Meinberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Hermes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Sengle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Drexelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Gebauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Neundorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dzemal","family":"Elezagic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Paulsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Streichert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas R.","family":"Klatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1001\/jama.2022.0470","article-title":"Association between 3 doses of mRNA COVID-19 vaccine and symptomatic infection caused by the SARS-CoV-2 omicron and delta variants","volume":"327","author":"Accorsi","year":"2022","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.3390\/nu13061760","article-title":"Calcifediol treatment and hospital mortality due to COVID-19: A cohort study","volume":"13","author":"Alcala-Diaz","year":"2021","journal-title":"Nutrients"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.880961","article-title":"Upregulating human cathelicidin antimicrobial peptide LL-37 expression may prevent severe COVID-19 inflammatory responses and reduce microthrombosis","volume":"13","author":"Aloul","year":"2022","journal-title":"Front. 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