{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:49:18Z","timestamp":1791600558262,"version":"4.3.4"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["CRG\/2021\/000190"],"award-info":[{"award-number":["CRG\/2021\/000190"]}],"id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009104","name":"Department of Health Research, India","doi-asserted-by":"publisher","award":["YSS\/2020\/000010\/PRCYSS"],"award-info":[{"award-number":["YSS\/2020\/000010\/PRCYSS"]}],"id":[{"id":"10.13039\/501100009104","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Herpes Simplex Virus Type 2 is a prevalent sexually transmitted pathogen that causes genital herpes and severe neurological complications, including meningitis and encephalitis. A major challenge in HSV-2 infection is the uncontrolled inflammatory response mediated by NLRP3 inflammasome activation, leading to pyroptosis and excessive cytokine secretion. Despite its significant clinical burden, the molecular mechanisms underlying HSV-2-induced inflammation remain poorly understood. Recent evidence suggests that microRNAs play a crucial role in regulating host immune responses and inflammasome activation. In this study, we investigate the regulatory role of miR-141 and miR-211 in modulating inflammasome activation and viral replication during HSV-2 infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>THP-1-derived macrophages were transfected with miR-141 or miR-211 mimics or scrambled controls before infection with HSV-2. Quantitative PCR and Western blot analysis were performed to assess the expression of NLRP3, CASP1, IL-1\u03b2, IL-18, and GSDM-D. Luciferase reporter assays were conducted to validate miRNA\u2013target interactions, and ELISA was used to quantify cytokine levels in culture supernatants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our results demonstrate that HSV-2 infection significantly downregulates miR-141 and miR-211, leading to enhanced NLRP3 inflammasome activation, increased caspase-1 cleavage, and excessive secretion of IL-1\u03b2 and IL-18, ultimately causing pyroptotic cell death. Transfection with miR-141 and miR-211 mimics restored miRNA expression, resulting in a marked suppression of inflammasome activation and inflammatory cytokine release, as well as significant inhibition of HSV-2 viral gene expression. Luciferase assays confirmed that miR-141 directly targets NLRP3, while miR-211 regulates CASP1, validating their roles as post-transcriptional repressors of inflammasome components.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings establish miR-141 and miR-211 as critical modulators of HSV-2-induced inflammasome activation, highlighting a novel miRNA-based regulatory mechanism. Restoring these miRNAs significantly reduces viral replication and inflammation, underscoring their potential as therapeutic targets for managing HSV-2-induced immunopathology. Future research should focus on <jats:italic>in vivo<\/jats:italic> validation and therapeutic optimization to develop miRNA-based interventions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2025.1602965","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T05:25:49Z","timestamp":1748496349000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection"],"prefix":"10.3389","volume":"15","author":[{"given":"Debashree","family":"Dass","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwesha","family":"Banerjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashwini","family":"More","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupam","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e05005","DOI":"10.7554\/eLife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs","volume":"4","author":"Agarwal","year":"2015","journal-title":"eLife"},{"key":"B2","unstructured":"Herpes simplex encephalitis\n          \n          \n            \n              Ak\n              A. K.\n            \n            \n              Bhutta\n              B. S.\n            \n            \n              Mendez\n              M. D.\n            \n          \n          Treasure Island (FL\n          StatPearls Publishing\n          StatPearls\n          \n          2025"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11091488","article-title":"Combinatorial effects of miRNAs in HSV-2 infection of macrophages: an in silico and in vitro integration approach","volume":"11","author":"Banerjee","year":"2023","journal-title":"Vaccines"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-10-359","article-title":"Herpes simplex virus type 2 seropositivity and relationship status among U.S. adults age 20 to 49: a population-based analysis","volume":"10","author":"Bauer","year":"2010","journal-title":"BMC Infect. Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.bbrc.2015.02.029","article-title":"NLRP3 inflammasome expression is driven by NF-\u03baB in cultured hepatocytes","volume":"458","author":"Boaru","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B6","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s13311-016-0433-7","article-title":"Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management","volume":"13","author":"Bradshaw","year":"2016","journal-title":"Neurother. J. Am. Soc Exp. Neurother."},{"key":"B7","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.imlet.2022.03.003","article-title":"A small molecule inhibitor of caspase-1 inhibits NLRP3 inflammasome activation and pyroptosis to alleviate gouty inflammation","volume":"244","author":"Cao","year":"2022","journal-title":"Immunol. Lett."},{"key":"B8","doi-asserted-by":"publisher","first-page":"7204","DOI":"10.18632\/oncotarget.23208","article-title":"Inflammatory responses and inflammation-associated diseases in organs","volume":"9","author":"Chen","year":"2018","journal-title":"Oncotarget"},{"key":"B9","doi-asserted-by":"publisher","first-page":"D127","DOI":"10.1093\/nar\/gkz757","article-title":"miRDB: an online database for prediction of functional microRNA targets","volume":"48","author":"Chen","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/v16091383","article-title":"HSV-2 manipulates autophagy through interferon pathway: A strategy for viral survival","volume":"16","author":"Dass","year":"2024","journal-title":"Viruses"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/v15020429","article-title":"miRNAs in herpesvirus infection: powerful regulators in small packages","volume":"15","author":"Dass","year":"2023","journal-title":"Viruses"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1002\/ana.410050103","article-title":"An explanation for the localization of herpes simplex encephalitis","volume":"5","author":"Davis","year":"1979","journal-title":"Ann. Neurol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1016\/j.tig.2022.02.006","article-title":"Emerging concepts of miRNA therapeutics: from cells to clinic","volume":"38","author":"Diener","year":"2022","journal-title":"Trends Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1002\/eji.201141550","article-title":"A clinical perspective of IL-1\u03b2 as the gatekeeper of inflammation","volume":"41","author":"Dinarello","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/nm.3893","article-title":"Inflammasomes: mechanism of action, role in disease, and therapeutics","volume":"21","author":"Guo","year":"2015","journal-title":"Nat. Med."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.838808","article-title":"Herpes simplex virus 1 induces microglia gasdermin D-dependent pyroptosis through activating the NLR family pyrin domain containing 3 inflammasome","volume":"13","author":"Hu","year":"2022","journal-title":"Front. Microbiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1023\/A:1011178225912","article-title":"Antiviral effect of red microalgal polysaccharides on Herpes simplex and Varicella zoster viruses","volume":"13","author":"Huleihel","year":"2001","journal-title":"J. Appl. Phycol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/s0022-3476(84)80994-4","article-title":"Herpes simplex viral pneumonitis in childhood","volume":"104","author":"Hull","year":"1984","journal-title":"J. Pediatr."},{"key":"B19","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1007\/s40265-021-01474-5","article-title":"MicroRNA mimics or inhibitors as antiviral therapeutic approaches against COVID-19","volume":"81","author":"Hum","year":"2021","journal-title":"Drugs"},{"key":"B20","doi-asserted-by":"publisher","first-page":"17972","DOI":"10.1038\/s41598-017-18225-w","article-title":"miRNA-36 inhibits KSHV, EBV, HSV-2 infection of cells via stifling expression of interferon induced transmembrane protein 1 (IFITM1)","volume":"7","author":"Hussein","year":"2017","journal-title":"Sci. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"438","DOI":"10.15698\/mic2016.09.528","article-title":"Genital herpes: insights into sexually transmitted infectious disease","volume":"3","author":"Jaishankar","year":"2016","journal-title":"Microb. Cell Graz Austria"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.112428","article-title":"Overexpression of NLRP12 enhances antiviral immunity and alleviates herpes simplex keratitis via pyroptosis\/IL-18\/IFN-\u03b3 signaling","volume":"137","author":"Jiang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1212\/01.wnl.0000191407.81333.00","article-title":"Etiology of aseptic meningitis and encephalitis in an adult population","volume":"66","author":"Kupila","year":"2006","journal-title":"Neurology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.bcp.2019.05.003","article-title":"AT-533, a Hsp90 inhibitor, attenuates HSV-1-induced inflammation","volume":"166","author":"Li","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/s41392-021-00687-0","article-title":"Pattern recognition receptors in health and diseases","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduction Targeting Ther."},{"key":"B26","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.jtos.2018.10.002","article-title":"Pathogenesis of herpes simplex keratitis: The host cell response and ocular surface sequelae to infection and inflammation","volume":"17","author":"Lobo","year":"2019","journal-title":"Ocul. Surf."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1007\/s12026-024-09503-7","article-title":"miR-141-3p attenuates inflammation and oxidative stress\u2013induced pulmonary fibrosis in ARDS via the Keap1\/Nrf2\/ARE signaling pathway","volume":"72","author":"Long","year":"2024","journal-title":"Immunol. Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"935","DOI":"10.1097\/OLQ.0b013e3180ca965a","article-title":"The epidemiology of herpes simplex virus type-2 infection among married\u00a0women in Mysore, India","volume":"34","author":"Madhivanan","year":"2007","journal-title":"Sex Transm. Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/s41575-018-0054-1","article-title":"Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis","volume":"15","author":"Man","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1016\/j.tim.2020.03.003","article-title":"Herpes simplex virus-1 in the brain: the dark side of a sneaky infection","volume":"28","author":"Marcocci","year":"2020","journal-title":"Trends Microbiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1365-2249.2011.04440.x","article-title":"The NLRP3 inflammasome in health and disease: the good, the bad and the ugly","volume":"166","author":"Menu","year":"2011","journal-title":"Clin. Exp. Immunol."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1155\/2009\/419539","article-title":"Silencing viral microRNA as a novel antiviral therapy","volume":"2009","author":"Moens","year":"2009","journal-title":"BioMed. Res. Int."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1038\/s41598-018-38473-8","article-title":"Synchronized Orchestration of miR-99b and let-7g Positively Regulates Rotavirus Infection by Modulating Autophagy","volume":"9","author":"Mukhopadhyay","year":"2019","journal-title":"Sci. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1080\/00365540701509881","article-title":"Herpes simplex virus type 2 infections of the central nervous system: A retrospective study of 49 patients","volume":"40","author":"Omland","year":"2008","journal-title":"Scand. J. Infect. Dis."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/v8060156","article-title":"The role of microRNAs in the pathogenesis of herpesvirus infection","volume":"8","author":"Piedade","year":"2016","journal-title":"Viruses"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-013-0414-8","article-title":"Update on herpes virus infections of the nervous system","volume":"13","author":"Steiner","year":"2013","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e0206239","DOI":"10.1371\/journal.pone.0206239","article-title":"miRWalk: An online resource for prediction of microRNA binding sites","volume":"13","author":"Sticht","year":"2018","journal-title":"PloS One"},{"key":"B38","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1038\/nature10759","article-title":"Inflammasomes in health and disease","volume":"481","author":"Strowig","year":"2012","journal-title":"Nature"},{"key":"B39","first-page":"57A","article-title":"Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret\u2019s","author":"Tyler","year":"2004","journal-title":"Herpes J. IHMF"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21010337","article-title":"Curcumin can decrease tissue inflammation and the severity of HSV-2 infection in the female reproductive mucosa","volume":"21","author":"Vitali","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/nrn3638","article-title":"Inflammasomes in the CNS","volume":"15","author":"Walsh","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e78085","DOI":"10.7554\/eLife.78085","article-title":"Mir204 and Mir211 suppress synovial inflammation and proliferation in rheumatoid arthritis by targeting Ssrp1","volume":"11","author":"Wang","year":"2022","journal-title":"eLife"},{"key":"B43","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.tibs.2022.10.002","article-title":"The NLRP3 inflammasome: activation and regulation","volume":"48","author":"Xu","year":"2023","journal-title":"Trends Biochem. Sci."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1080\/08916934.2023.2220988","article-title":"miR-141-3p alleviates ulcerative colitis by targeting SUGT1 to inhibit colonic epithelial cell pyroptosis","volume":"56","author":"Yan","year":"2023","journal-title":"Autoimmunity"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01687-y","article-title":"The role of inflammasomes in human diseases and their potential as therapeutic targets","volume":"9","author":"Yao","year":"2024","journal-title":"Signal Transduction Targeting Ther."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1177\/03946320241234736","article-title":"Macrophage-derived exosomal miRNA-141 triggers endothelial cell pyroptosis by targeting NLRP3 to accelerate sepsis progression","volume":"38","author":"Zhan","year":"2024","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"160","DOI":"10.3892\/mmr.2023.13047","article-title":"The NLRP3 inflammasome in viral infection (Review)","volume":"28","author":"Zheng","year":"2023","journal-title":"Mol. Med. Rep."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2670","DOI":"10.1080\/21505594.2021.1982373","article-title":"Pathogenesis and virulence of herpes simplex virus","volume":"12","author":"Zhu","year":"2021","journal-title":"Virulence"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1602965\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T05:25:51Z","timestamp":1748496351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2025.1602965\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,29]]},"references-count":48,"alternative-id":["10.3389\/fcimb.2025.1602965"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2025.1602965","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,29]]},"article-number":"1602965"}}