MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection
IntroductionHerpes 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...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| author | Debashree Dass Debashree Dass Anwesha Banerjee Ashwini More Anupam Mukherjee Anupam Mukherjee Anupam Mukherjee Anupam Mukherjee |
| author_facet | Debashree Dass Debashree Dass Anwesha Banerjee Ashwini More Anupam Mukherjee Anupam Mukherjee Anupam Mukherjee Anupam Mukherjee |
| author_sort | Debashree Dass |
| collection | DOAJ |
| description | IntroductionHerpes 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.MethodsTHP-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-1β, IL-18, and GSDM-D. Luciferase reporter assays were conducted to validate miRNA–target interactions, and ELISA was used to quantify cytokine levels in culture supernatants.ResultsOur 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-1β 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.DiscussionThese 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 in vivo validation and therapeutic optimization to develop miRNA-based interventions. |
| format | Article |
| id | doaj-art-6dfd8f21ecc14fa392d89ec380aa2e7e |
| institution | DOAJ |
| issn | 2235-2988 |
| language | English |
| publishDate | 2025-05-01 |
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| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj-art-6dfd8f21ecc14fa392d89ec380aa2e7e2025-08-20T03:21:31ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882025-05-011510.3389/fcimb.2025.16029651602965MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infectionDebashree Dass0Debashree Dass1Anwesha Banerjee2Ashwini More3Anupam Mukherjee4Anupam Mukherjee5Anupam Mukherjee6Anupam Mukherjee7ICMR-National Institute of Translational Virology and AIDS Research, Pune, IndiaSavitribai Phule Pune University, Pune, IndiaICMR-National Institute of Translational Virology and AIDS Research, Pune, IndiaICMR-National Institute of Translational Virology and AIDS Research, Pune, IndiaICMR-National Institute of Translational Virology and AIDS Research, Pune, IndiaSavitribai Phule Pune University, Pune, IndiaAcSIR - Academy of Scientific & Innovative Research, Ghaziabad, IndiaICMR-National Institute of Virology, Pune, IndiaIntroductionHerpes 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.MethodsTHP-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-1β, IL-18, and GSDM-D. Luciferase reporter assays were conducted to validate miRNA–target interactions, and ELISA was used to quantify cytokine levels in culture supernatants.ResultsOur 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-1β 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.DiscussionThese 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 in vivo validation and therapeutic optimization to develop miRNA-based interventions.https://www.frontiersin.org/articles/10.3389/fcimb.2025.1602965/fullHSV-2inflammationNLRP3 inflammasomepyroptosiscaspase-1IL-1β |
| spellingShingle | Debashree Dass Debashree Dass Anwesha Banerjee Ashwini More Anupam Mukherjee Anupam Mukherjee Anupam Mukherjee Anupam Mukherjee MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection Frontiers in Cellular and Infection Microbiology HSV-2 inflammation NLRP3 inflammasome pyroptosis caspase-1 IL-1β |
| title | MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection |
| title_full | MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection |
| title_fullStr | MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection |
| title_full_unstemmed | MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection |
| title_short | MicroRNAs as regulators of NLRP3 inflammasome activation in herpes simplex virus type 2 infection |
| title_sort | micrornas as regulators of nlrp3 inflammasome activation in herpes simplex virus type 2 infection |
| topic | HSV-2 inflammation NLRP3 inflammasome pyroptosis caspase-1 IL-1β |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2025.1602965/full |
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