{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T11:40:35Z","timestamp":1778931635838,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011749","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T00:00:00Z","timestamp":1716422400000}}],"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T00:00:00Z","timestamp":1715558400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["RTI2018-101936-B-I00"],"award-info":[{"award-number":["RTI2018-101936-B-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["RD21\/0017\/0001 TERAV"],"award-info":[{"award-number":["RD21\/0017\/0001 TERAV"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["FPI grant"],"award-info":[{"award-number":["FPI grant"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FIMA","award":["becas AC"],"award-info":[{"award-number":["becas AC"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Hepatitis delta virus (HDV) infection represents the most severe form of human viral hepatitis; however, the mechanisms underlying its pathology remain incompletely understood. We recently developed an HDV mouse model by injecting adeno-associated viral vectors (AAV) containing replication-competent HBV and HDV genomes. This model replicates many features of human infection, including liver injury. Notably, the extent of liver damage can be diminished with anti-TNF-\u03b1 treatment. Here, we found that TNF-\u03b1 is mainly produced by macrophages. Downstream of the TNF-\u03b1 receptor (TNFR), the receptor-interacting serine\/threonine-protein kinase 1 (RIPK1) serves as a cell fate regulator, playing roles in both cell survival and death pathways. In this study, we explored the function of RIPK1 and other host factors in HDV-induced cell death. We determined that the scaffolding function of RIPK1, and not its kinase activity, offers partial protection against HDV-induced apoptosis. A reduction in RIPK1 expression in hepatocytes through CRISPR-Cas9-mediated gene editing significantly intensifies HDV-induced damage. Contrary to our expectations, the protective effect of RIPK1 was not linked to TNF-\u03b1 or macrophage activation, as their absence did not alter the extent of damage. Intriguingly, in the absence of RIPK1, macrophages confer a protective role. However, in animals unresponsive to type-I IFNs, RIPK1 downregulation did not exacerbate the damage, suggesting RIPK1\u2019s role in shielding hepatocytes from type-I IFN-induced cell death. Interestingly, while the damage extent is similar between IFN\u03b1\/\u03b2R KO and wild type mice in terms of transaminase elevation, their cell death mechanisms differ. In conclusion, our findings reveal that HDV-induced type-I IFN production is central to inducing hepatocyte death, and RIPK1\u2019s scaffolding function offers protective benefits. Thus, type-I IFN together with TNF-\u03b1, contribute to HDV-induced liver damage. These insights may guide the development of novel therapeutic strategies to mitigate HDV-induced liver damage and halt disease progression.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011749","type":"journal-article","created":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T13:39:53Z","timestamp":1715607593000},"page":"e1011749","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protective role of RIPK1 scaffolding against HDV-induced hepatocyte cell death and the significance of cytokines in mice"],"prefix":"10.1371","volume":"20","author":[{"given":"Graci\u00e1n","family":"Camps","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheila","family":"Maestro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Torella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego","family":"Herrero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla","family":"Usai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3332-5667","authenticated-orcid":true,"given":"Martin","family":"Bilbao-Arribas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Aldaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Olag\u00fce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Africa","family":"Vales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lester","family":"Su\u00e1rez-Amar\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Aldabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1600-4562","authenticated-orcid":true,"given":"Gloria","family":"Gonzalez-Aseguinolaza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,5,13]]},"reference":[{"key":"ppat.1011749.ref001","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nrgastro.2016.126","article-title":"Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options.","volume":"13","author":"FA Lempp","year":"2016","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"ppat.1011749.ref002","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/apt.15521","article-title":"Long-term clinical outcomes in patients with chronic hepatitis delta: the role of persistent viraemia","volume":"51","author":"A Palom","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"ppat.1011749.ref003","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.jhep.2020.06.037","article-title":"The burden of hepatitis D\u2014defogging the epidemiological horizon","volume":"73","author":"H. Wedemeyer","year":"2020","journal-title":"J Hepatol"},{"key":"ppat.1011749.ref004","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.jhep.2020.04.008","article-title":"The global prevalence of hepatitis D virus infection: Systematic review and meta-analysis","volume":"73","author":"AJ Stockdale","year":"2020","journal-title":"J Hepatol"},{"key":"ppat.1011749.ref005","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1053\/j.gastro.2018.09.058","article-title":"Pathogenesis of and New Therapies for Hepatitis D","volume":"156","author":"C Koh","year":"2019","journal-title":"Gastroenterology"},{"key":"ppat.1011749.ref006","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/hep.1840130508","article-title":"Direct evidence for cytotoxicity associated with expression of hepatitis delta virus antigen","volume":"13","author":"SM Cole","year":"1991","journal-title":"Hepatology"},{"key":"ppat.1011749.ref007","doi-asserted-by":"crossref","first-page":"100098","DOI":"10.1016\/j.jhepr.2020.100098","article-title":"TNF- alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection","volume":"2","author":"C Usai","year":"2020","journal-title":"JHEP Rep"},{"key":"ppat.1011749.ref008","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1111\/jvh.12895","article-title":"Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection.","volume":"25","author":"G Ricco","year":"2018","journal-title":"J Viral Hepat"},{"key":"ppat.1011749.ref009","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1053\/j.gastro.2019.02.003","article-title":"Mutations in hepatitis D virus allow it to escape detection by CD8+ T cells and evolve at the population level","volume":"156","author":"H Karimzadeh","year":"2019","journal-title":"Gastroenterology"},{"key":"ppat.1011749.ref010","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1053\/j.gastro.2019.01.035","article-title":"Hepatitis D Virus-Specific CD8+ T Cells Have a Memory-Like Phenotype Associated With Viral Immune Escape in Patients With Chronic Hepatitis D Virus Infection","volume":"156","author":"H Kefalakes","year":"2019","journal-title":"Gastroenterology"},{"key":"ppat.1011749.ref011","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1093\/infdis\/jiy549","article-title":"Detection of a broad range of Low-level major histocompatibility complex class II- restricted, Hepatitis Delta virus (HDV)-specific T-cell responses regardless of clinical status.","volume":"219","author":"J Landahl","year":"2019","journal-title":"J Infect Dis"},{"key":"ppat.1011749.ref012","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1053\/j.gastro.2021.07.027","article-title":"Liver- Resident Bystander CD8+ T Cells Contribute to Liver Disease Pathogenesis in Chronic Hepatitis D Virus Infection","volume":"161","author":"H Kefalakes","year":"2021","journal-title":"Gastroenterology"},{"key":"ppat.1011749.ref013","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.3390\/cells10113253","article-title":"Hepatitis-D Virus Infection Is Not Impaired by Innate Immunity but Increases Cytotoxic T-Cell Activity.","volume":"10","author":"SM Altstetter","year":"2021","journal-title":"Cells"},{"key":"ppat.1011749.ref014","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jhep.2015.03.011","article-title":"Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection","volume":"63","author":"K Giersch","year":"2015","journal-title":"J Hepatol"},{"key":"ppat.1011749.ref015","doi-asserted-by":"crossref","first-page":"e1004840","DOI":"10.1371\/journal.ppat.1004840","article-title":"Hepatitis D Virus Infection of Mice Expressing Human Sodium Taurocholate Co-transporting Polypeptide.","volume":"11","author":"W He","year":"2015","journal-title":"PLoS Pathog."},{"key":"ppat.1011749.ref016","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.jhep.2017.05.010","article-title":"A new HDV mouse model identifies mitochondrial antiviral signaling protein (MAVS) as a key player in IFN-\u03b2 induction.","volume":"67","author":"L Su\u00e1rez-Amar\u00e1n","year":"2017","journal-title":"J Hepatol"},{"key":"ppat.1011749.ref017","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1111\/jgh.14617","article-title":"The balance of type 1 and type 2 immune responses in the contexts of hepatitis B infection and hepatitis D infection","volume":"34","author":"EC Townsend","year":"2019","journal-title":"J Gastroenterol Hepatol"},{"key":"ppat.1011749.ref018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-030-49844-3_1","article-title":"Protein Kinase-Mediated Decision Between the Life and Death","volume":"1275","author":"A. 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