{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T20:29:45Z","timestamp":1788899385920,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012167","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T00:00:00Z","timestamp":1715040000000}}],"reference-count":75,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T00:00:00Z","timestamp":1714003200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI124493"],"award-info":[{"award-number":["AI124493"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015691","name":"Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI168003"],"award-info":[{"award-number":["AI168003"]}],"id":[{"id":"10.13039\/100015691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Dengue virus (DENV) is a medically important flavivirus causing an estimated 50\u2013100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1\u03b2 in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1\u03b2. Lastly, we show that caspase-1\/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012167","type":"journal-article","created":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T13:50:17Z","timestamp":1714053017000},"page":"e1012167","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection"],"prefix":"10.1371","volume":"20","author":[{"given":"Marcus P.","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan Y. W.","family":"Juan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Pahmeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai S.","family":"Chelluri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Castillo-Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie F.","family":"Blanc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott B.","family":"Biering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell E.","family":"Vance","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7238-4037","authenticated-orcid":true,"given":"Eva","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,25]]},"reference":[{"issue":"9","key":"ppat.1012167.ref001","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1038\/s41564-019-0476-8","article-title":"The current and future global distribution and population at risk of dengue.","volume":"4","author":"JP Messina","year":"2019","journal-title":"Nat Microbiol"},{"issue":"528","key":"ppat.1012167.ref002","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aax4144","article-title":"Mapping global variation in dengue transmission intensity.","volume":"12","author":"L Cattarino","year":"2020","journal-title":"Sci Transl Med."},{"key":"ppat.1012167.ref003","unstructured":"World Health Organization. Dengue guidelines for diagnosis, treatment, prevention and control: new edition [Internet]. World Health Organization; 2009. Report No.: WHO\/HTM\/NTD\/DEN\/2009.1. Available from: https:\/\/apps.who.int\/iris\/handle\/10665\/44188"},{"key":"ppat.1012167.ref004","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.coviro.2020.07.010","article-title":"Understanding immunopathology of severe dengue: lessons learnt from sepsis.","volume":"43","author":"JA Aguilar-Brise\u00f1o","year":"2020","journal-title":"Curr Opin Virol.Aug 1"},{"issue":"5","key":"ppat.1012167.ref005","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s00281-017-0625-1","article-title":"Immune Mediated Cytokine Storm and Its Role in Severe Dengue.","volume":"39","author":"A Srikiatkhachorn","year":"2017","journal-title":"Semin Immunopathol"},{"issue":"6","key":"ppat.1012167.ref006","doi-asserted-by":"crossref","first-page":"e2021055522","DOI":"10.1542\/peds.2021-055522","article-title":"Dengue: A Growing Problem With New Interventions","volume":"149","author":"JM 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viral RNA replication but not for formation of the membranous replication organelle","volume":"15","author":"A P\u0142aszczyca","year":"2019","journal-title":"PLoS Pathog"},{"issue":"1","key":"ppat.1012167.ref010","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-virology-101416-041848","article-title":"The Good, the Bad, and the Shocking: The Multiple Roles of Dengue Virus Nonstructural Protein 1 in Protection and Pathogenesis.","volume":"5","author":"DR Glasner","year":"2018","journal-title":"Annu Rev Virol."},{"issue":"19","key":"ppat.1012167.ref011","doi-asserted-by":"crossref","first-page":"8003","DOI":"10.1073\/pnas.1017338108","article-title":"Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein","volume":"108","author":"I Gutsche","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1012167.ref012","first-page":"6756","article-title":"CryoEM structures of the multimeric secreted 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Hornung","year":"2009","journal-title":"Nature"},{"key":"ppat.1012167.ref032","article-title":"Functional degradation: A mechanism of NLRP1 inflammasome activation by diverse pathogen enzymes","author":"A Sandstrom","year":"2019","journal-title":"Science"},{"key":"ppat.1012167.ref033","doi-asserted-by":"crossref","first-page":"e60609","DOI":"10.7554\/eLife.60609","article-title":"Diverse viral proteases activate the NLRP1 inflammasome.","volume":"10","author":"BV Tsu","year":"2021","journal-title":"eLife"},{"issue":"6151","key":"ppat.1012167.ref034","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1126\/science.1240988","article-title":"Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock","volume":"341","author":"JA Hagar","year":"2013","journal-title":"Science"},{"issue":"6151","key":"ppat.1012167.ref035","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1126\/science.1240248","article-title":"Noncanonical inflammasome activation 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Kayagaki","year":"2021","journal-title":"Nature"},{"issue":"1","key":"ppat.1012167.ref039","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.immuni.2017.11.013","article-title":"The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages","volume":"48","author":"CL Evavold","year":"2018","journal-title":"Immunity"},{"issue":"6290","key":"ppat.1012167.ref040","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1126\/science.aaf3036","article-title":"An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells","volume":"352","author":"I Zanoni","year":"2016","journal-title":"Science"},{"key":"ppat.1012167.ref041","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1038\/s41467-023-36626-6","article-title":"Gasdermin-D activation promotes NLRP3 activation and host resistance to Leishmania infection.","volume":"14","author":"KSG de S\u00e1","year":"2023","journal-title":"Nat 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Wang","year":"2021","journal-title":"Science"},{"issue":"2","key":"ppat.1012167.ref045","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41590-021-01091-0","article-title":"Innate immunity: the first line of defense against SARS-CoV-2","volume":"23","author":"MS Diamond","year":"2022","journal-title":"Nat Immunol"},{"issue":"4","key":"ppat.1012167.ref046","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.immuni.2009.02.006","article-title":"NLRP3 (NALP3\/CIAS1\/Cryopyrin) mediates key innate and healing responses to influenza A virus via the regulation of caspase-1.","volume":"30","author":"PG Thomas","year":"2009","journal-title":"Immunity"},{"issue":"11","key":"ppat.1012167.ref047","doi-asserted-by":"crossref","first-page":"e1003039","DOI":"10.1371\/journal.ppat.1003039","article-title":"IL-1\u03b2 Signaling Promotes CNS-Intrinsic Immune Control of West Nile Virus Infection.","volume":"8","author":"HJ Ramos","year":"2012","journal-title":"PLoS 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