{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:14:30Z","timestamp":1792793670239,"version":"4.5.0"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"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. Immunol."],"abstract":"<jats:p>SARS-CoV-2 disrupts cellular homeostasis, including the autophagy-lysosome pathway (ALP), a critical component of innate immunity and viral clearance. By subverting autophagy, SARS-CoV-2 proteins such as ORF3a, ORF7a, and NSP6 inhibit autophagosome-lysosome (APG-L) fusion, generating \u201cincomplete autophagy\u201d that permits viral persistence and drives hyperinflammation. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, has emerged as a central player in the host response to coronavirus infection. TFEB orchestrates the expression of genes required for lysosomal function and autophagic flux while also shaping immune processes, including cytokine production, interferon-stimulated gene expression, and inflammasome clearance. This mini review synthesizes current knowledge on the TFEB-ALP axis in COVID-19 pathogenesis, highlighting its influence on acute immunopathology and its potential contribution to post-acute sequelae (Long COVID). Restoring TFEB activity and autophagic flux may counteract SARS-CoV-2 evasion strategies and restrain aberrant inflammatory responses. Harnessing the TFEB-autophagy pathway as a host-directed therapeutic strategy could help rebalance immune homeostasis, limit tissue damage during acute infection, and mitigate persistent inflammatory sequelae in Long COVID.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1708364","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T06:28:37Z","timestamp":1764311317000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Dysregulated TFEB\u2013autophagy-lysosome pathway links acute COVID-19 immunopathology to Long COVID sequelae"],"prefix":"10.3389","volume":"16","author":[{"given":"Magdalena","family":"Gabig-Cimi\u0144ska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e00187-20","DOI":"10.1128\/JCM.00187-20","article-title":"The emergence of a novel coronavirus (SARS-CoV-2), their biology and therapeutic options","volume":"58","author":"Khan","year":"2020","journal-title":"J Clin Microbiol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2000929","article-title":"A novel coronavirus emerging in China \u2013 Key questions for impact assessment","volume":"382","author":"Munster","year":"2020","journal-title":"New Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017","article-title":"A novel coronavirus from patients with pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"New Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.devcel.2020.12.010","article-title":"ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation","volume":"56","author":"Miao","year":"2021","journal-title":"Dev Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.1204592","article-title":"TFEB links autophagy to lysosomal biogenesis","volume":"332","author":"Settembre","year":"2011","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3565","article-title":"Signals for the lysosome: a control center for cellular clearance and energy metabolism","volume":"14","author":"Settembre","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1174447","article-title":"A gene network regulating lysosomal biogenesis and function","volume":"325","author":"Sardiello","year":"2009","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.immuni.2014.05.002","article-title":"Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes","volume":"40","author":"Visvikis","year":"2014","journal-title":"Immunity"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2016.1179405","article-title":"TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages","volume":"12","author":"Pastore","year":"2016","journal-title":"Autophagy"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1313943","article-title":"Emerging roles for TFEB in the immune response and inflammation","volume":"14","author":"Brady","year":"2018","journal-title":"Autophagy"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3196","article-title":"The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen-presentation pathways","volume":"16","author":"Samie","year":"2015","journal-title":"Nat Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.12.003","article-title":"Key roles of miT transcription factors in innate immunity and inflammation","volume":"41","author":"Irazoqui","year":"2020","journal-title":"Trends Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e0102023","DOI":"10.1128\/mbio.01020-23","article-title":"Bidirectional interplay between SARS-CoV-2 and autophagy","volume":"14","author":"Zhou","year":"2023","journal-title":"mBio"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2084686","article-title":"SARS-CoV-2 ORF7a initiates autophagy and limits autophagosome\u2013lysosome fusion via SNAP29 degradation to promote virus replication","volume":"19","author":"Hou","year":"2023","journal-title":"Autophagy"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00754-24","article-title":"SARS-CoV-2 NSP6 reduces autophagosome size and affects viral replication via sigma-1 receptor","volume":"98","author":"Zhang","year":"2024","journal-title":"J Virol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/s41420-019-0181-7","article-title":"SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes","volume":"5","author":"Shi","year":"2019","journal-title":"Cell Death Discov"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112286","article-title":"Coronavirus subverts ER-phagy by hijacking FAM134B and ATL3 into p62 condensates to facilitate viral replication","volume":"42","author":"Tan","year":"2023","journal-title":"Cell Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2022.102388","article-title":"SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases","volume":"54","author":"Liu","year":"2022","journal-title":"Redox Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00011-23","article-title":"SARS-coV-2 ORF8 protein induces endoplasmic reticulum stress-like responses and facilitates virus replication by triggering calnexin: an unbiased study","volume":"97","author":"Wang","year":"2023","journal-title":"J Virol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03314-24","article-title":"RAB5 is a host dependency factor for the generation of SARS-CoV-2 replication organelles","volume":"16","author":"Chen","year":"2025","journal-title":"mBio"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00002-25","article-title":"Syntaxin-6 restricts SARS-CoV-2 infection by facilitating virus trafficking to the autophagy-lysosomal degradation pathway","volume":"99","author":"Sun","year":"2025","journal-title":"J Virol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004502","article-title":"Coronavirus cell entry occurs through the endo-\/lysosomal pathway in a proteolysis-dependent manner","volume":"10","author":"Burkard","year":"2014","journal-title":"PloS Pathog"},{"key":"B23","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/s41419-018-0917-y","article-title":"SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death","volume":"9","author":"Yue","year":"2018","journal-title":"Cell Death Dis"},{"key":"B24","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/tra.12617","article-title":"Lysosome: The metabolic signaling hub","volume":"20","author":"Lamming","year":"2019","journal-title":"Traffic"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3114","article-title":"Lysosomal calcium signaling regulates autophagy via calcineurin and TFEB","volume":"17","author":"Medina","year":"2016","journal-title":"Nat Cell Biol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3312","DOI":"10.1038\/s41467-018-05862-6","article-title":"mTOR-dependent phosphorylation controls TFEB nuclear export","volume":"9","author":"Napolitano","year":"2018","journal-title":"Nat Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.32","article-title":"A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB","volume":"31","author":"Settembre","year":"2012","journal-title":"EMBO J"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201505966","article-title":"The awesome lysosome","volume":"8","author":"Ballabio","year":"2016","journal-title":"EMBO Mol Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nri3532","article-title":"Autophagy in infection, inflammation and immunity","volume":"13","author":"Deretic","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41421-020-0141-7","article-title":"Lysosome biology in autophagy","volume":"6","author":"Yim","year":"2020","journal-title":"Cell Discov"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3109\/08830185.2014.936587","article-title":"The roles of lysosomes in inflammation and autoimmune diseases","volume":"34","author":"Ge","year":"2015","journal-title":"Int Rev Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/2326409816650465","article-title":"Lysosomes, lysosomal storage diseases, and inflammation","volume":"4","author":"Simonaro","year":"2016","journal-title":"J Inborn Errors Metab Screen"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nri3035","article-title":"Immune regulation: Lysosomes at the heart of inflammation","volume":"11","author":"Bordon","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"ra44","DOI":"10.1126\/scisignal.2001450","article-title":"Identification of a lysosomal pathway that modulates glucocorticoid signaling and the inflammatory response","volume":"4","author":"He","year":"2013","journal-title":"Sci Signal"},{"key":"B35","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1146\/annurev.me.18.020167.000525","article-title":"The role of lysosomes in inflammation and disease","volume":"18","author":"Weissmann","year":"1967","journal-title":"Annu Rev Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.32607\/20758251-2009-1-3-125-135","article-title":"Study of molecular mechanisms involved in the pathogenesis of immune-mediated inflammatory diseases, using psoriasis as a model","volume":"1","author":"Piruzian","year":"2009","journal-title":"Acta Naturae"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.04.052","article-title":"An evolutionarily conserved PLC-PKD-TFEB pathway for host defense","volume":"15","author":"Najibi","year":"2016","journal-title":"Cell Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21155434","article-title":"Autophagy-related pathways in psoriasis and chronic inflammation: implications for systemic immune responses","volume":"21","author":"Gabig-Cimi\u0144ska","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803458","article-title":"Autophagy and its role in MHC-mediated antigen presentation","volume":"182","author":"Crotzer","year":"2009","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00460-13","article-title":"How positive-strand RNA viruses benefit from autophagosome maturation","volume":"87","author":"Richards","year":"2013","journal-title":"J Virol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e1005018","DOI":"10.1371\/journal.ppat.1005018","article-title":"Human immunodeficiency virus type 1 nef inhibits autophagy through transcription factor EB sequestration","volume":"11","author":"Campbell","year":"2015","journal-title":"PloS Pathog"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.903498","article-title":"Autophagy hijacking in PBMC from COVID-19 patients results in lymphopenia","volume":"13","author":"Barbati","year":"2022","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cophys.2022.100596","article-title":"Autophagy in severe acute respiratory syndrome coronavirus 2 infection","volume":"29","author":"Chen","year":"2022","journal-title":"Curr Opin Physiol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1582783","article-title":"Acute COVID-19 and LongCOVID syndrome \u2013 molecular implications for therapeutic strategies - review","volume":"16","author":"Michalak","year":"2025","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13412-5","article-title":"Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study","volume":"361","author":"Peiris","year":"2003","journal-title":"Lancet"},{"key":"B46","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s12931-025-03258-x","article-title":"Complement activity and autophagy are dysregulated in the lungs of patients with nonresolvable COVID-19 requiring lung transplantation","volume":"26","author":"Shivshankar","year":"2025","journal-title":"Respir Res"},{"key":"B47","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s40425-018-0343-9","article-title":"Cytokine release syndrome","volume":"6","author":"Shimabukuro-Vornhagen","year":"2018","journal-title":"J Immunother Cancer"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.20255","article-title":"An interferon-gamma-related cytokine storm in SARS patients","volume":"75","author":"Huang","year":"2005","journal-title":"J Med Virol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1002\/path.2067","article-title":"Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS","volume":"210","author":"He","year":"2006","journal-title":"J Pathol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3390\/cells12091282","article-title":"Autophagy receptor p62 regulates SARS-coV-2-induced inflammation in COVID-19","volume":"12","author":"Paunovic","year":"2023","journal-title":"Cells"},{"key":"B51","doi-asserted-by":"publisher","first-page":"eadg7942","DOI":"10.1126\/science.adg7942","article-title":"Persistent complement dysregulation with signs of thromboinflammation in active Long Covid","volume":"383","author":"Cervia-Hasler","year":"2024","journal-title":"Science"},{"key":"B52","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.cell.2022.01.014","article-title":"Multiple early factors anticipate post-acute COVID-19 sequelae","volume":"185","author":"Su","year":"2022","journal-title":"Cell"},{"key":"B53","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/s44324-024-00038-x","article-title":"Mitochondrial dysfunction in acute and post-acute phases of COVID-19 and risk of non-communicable diseases","volume":"2","author":"Madsen","year":"2024","journal-title":"NPJ Metab Health Dis"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-024-01165-5","article-title":"Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches","volume":"46","author":"Molnar","year":"2024","journal-title":"Geroscience"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2025.2528167","article-title":"Mitochondrial function is impaired in long COVID patients","volume":"57","author":"Macnaughtan","year":"2025","journal-title":"Ann Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2024.1406635","article-title":"Mitochondria in COVID-19: from cellular and molecular mechanisms to pathophysiological implications","volume":"15","author":"Rurek","year":"2024","journal-title":"Front Physiol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1597370","article-title":"Mitochondrial metabolic rescue in post-COVID-19 syndrome: MR spectroscopy insights and precision nutritional therapeutics","volume":"16","author":"Chen","year":"2025","journal-title":"Front Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3390\/v16091491","article-title":"Is autophagy a friend or foe in SARS-coV-2 infection","volume":"16","author":"Khan","year":"2024","journal-title":"Viruses"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0282-0","article-title":"Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro","volume":"30","author":"Wang","year":"2020","journal-title":"Cell Res"},{"key":"B60","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41421-020-0156-0","article-title":"Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro","volume":"6","author":"Liu","year":"2020","journal-title":"Cell Discov"},{"key":"B61","article-title":"COVID-19 Treatment and Management Guidelines. Recommendation against hydroxychloroquine (with or without azithromycin)","year":"2025"},{"key":"B62","article-title":"Drugs to prevent COVID-19: living guideline. Strong recommendation against hydroxychloroquine for prophylaxis","year":"2023"},{"key":"B63","article-title":"COVID-19 treatment guidelines (final archived PDF, feb 2024)","year":"2024"},{"key":"B64","doi-asserted-by":"publisher","first-page":"e1004428","DOI":"10.1371\/journal.pmed.1004428","article-title":"Evaluation of hydroxychloroquine or chloroquine for the prevention of COVID-19 (COPCOV): A double-blind, randomized, placebo-controlled trial","volume":"21","author":"Schilling","year":"2024","journal-title":"PloS Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1708364\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T06:28:40Z","timestamp":1764311320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1708364\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":64,"alternative-id":["10.3389\/fimmu.2025.1708364"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1708364","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"article-number":"1708364"}}