{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T06:47:04Z","timestamp":1767682024737,"version":"3.48.0"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009563","name":"Fundaci\u00f3n para la Formaci\u00f3n e Investigaci\u00f3n Sanitarias de la Regi\u00f3n de Murcia","doi-asserted-by":"publisher","award":["CP23\/00049"],"award-info":[{"award-number":["CP23\/00049"]}],"id":[{"id":"10.13039\/501100009563","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Since the emergence of SARS-CoV-2 in late 2019, substantial efforts have been made to understand its mechanisms of pathogenicity. Although angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for viral entry, the complexity of the host immune response to different Spike protein conformations and variants remains poorly understood. Using zebrafish larvae as an\n                    <jats:italic>in vivo<\/jats:italic>\n                    model, we show that the monomeric S1 domain of the Omicron variant triggers a potent proinflammatory response characterized by elevated Nfkb activity and increased expression of key cytokines, despite reduced recruitment and expansion of neutrophils and macrophages. Notably, monomeric S1 Omicron also promotes neutrophil cell death, suggesting an alternative mechanism of immune modulation. In contrast, the trimeric form of the Spike protein fails to induce significant inflammation or emergency hematopoiesis, likely due to its efficient neutralization by endogenous Ace2. Our results revealed that both zebrafish and human ACE2 exert a dual anti-inflammatory role: indirectly through the production of angiotensin-(1-7), and directly by binding and neutralizing the trimeric Spike. These results provide new insights into variant-specific immune responses and the multifaceted role of ACE2 in modulating SARS-CoV-2-induced cytokine storm syndrome.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1667880","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T06:42:44Z","timestamp":1767681764000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual role of ACE2 in regulating inflammation triggered by Omicron S1 and other SARS-CoV-2 Spike variants"],"prefix":"10.3389","volume":"16","author":[{"given":"Annamaria","family":"Pedoto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan M.","family":"Lozano-Gil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda","family":"Oca\u00f1a-Esparza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana M.","family":"Conesa-Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergio","family":"Candel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda L.","family":"Cayuela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoriano","family":"Mulero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylwia D.","family":"Tyrkalska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"114434","DOI":"10.1016\/j.jviromet.2021.114434","article-title":"COVID-19: Invasion, pathogenesis and possible cure - A review","volume":"300","author":"Nitin","year":"2022","journal-title":"J Virol Methods"},{"key":"B2","doi-asserted-by":"publisher","first-page":"4541","DOI":"10.1038\/s41467-020-18319-6","article-title":"Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor","volume":"11","author":"Yang","year":"2020","journal-title":"Nat Commun"},{"key":"B3","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.cell.2022.01.001","article-title":"Receptor binding and complex structures of human ACE2 to spike RBD from omicron and delta SARS-CoV-2","volume":"185","author":"Han","year":"2022","journal-title":"Cell"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s10096-020-04138-6","article-title":"COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection","volume":"40","author":"Beyerstedt","year":"2021","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2507","article-title":"Cryo-EM structure of the 2019-nCoV","volume":"367","author":"Wrapp","year":"2020","journal-title":"spike prefusion conformation. 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