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TV has been shown to secrete extracellular vesicles (TV-EVs) to regulate intercellular communication between parasites and host immune response; however, the mechanisms by innate immunity against TV-EVs are largely unknown. Herein, we aim to investigate the molecular mechanisms of inflammation induced by TV-EVs and identify novel proteins modulating the immune response in host cells. Firstly, the morphological characteristics of TV-EVs have been analyzed by transmission electron microscope (TEM) and nanoparticle tracking analysis, revealing that the vesicles are round-shaped bilayer membrane structures with size mostly about 100\u2013120\u2009nm. Additionally, the internalization of TV-EVs by host cells has been validated through immunofluorescence and TEM analysis. The multiplex immunoassay identified that TV-EVs induce the secretion of inflammatory cytokines, including CXCL1, IL-6, IL-8 and MIP-1\u03b2 in THP-1 macrophages and ectocervical cells (Ect). Mechanistically, TV-EVs induce TLR3 overexpression to activate the NF-\u03baB\/NLRP3 pathway in THP-1 macrophages. Additionally, TV-EVs activate the PI3K-mediated NF-\u03baB, p38 MAPK and ERK pathways in Ect. Moreover, TV-EV-induced TLR3 overexpression positively regulates the PI3K and NF-\u03baB pathways, while simultaneously suppressing the p38 MAPK and ERK pathways in Ect. Proteomic analysis identified that TV-EVs upregulate MICB and TRAF3IP2, which are also positively regulated by TLR3 and involved in TV-EV-induced inflammatory cascade. Altogether, this study significantly advances our understanding of the immunomodulatory roles of TV-EVs in host cells, paving the way for future treatment of trichomoniasis and TV-associated STIs.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013216","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T17:58:07Z","timestamp":1748887087000},"page":"e1013216","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Trichomonas vaginalis extracellular vesicles activate the NLRP3 inflammasome and TLR3-mediated inflammatory cascades in host cells"],"prefix":"10.1371","volume":"21","author":[{"given":"Ching-Yun","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Fang","family":"Chiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichieh Julie","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Ming","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Jung","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuo-Lun","family":"Lan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ling","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Chun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Fu F.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ning","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4038-1579","authenticated-orcid":true,"given":"Kuo-Yang","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"ppat.1013216.ref001","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1042\/bse0510161","article-title":"Trichomonas vaginalis: current understanding of host-parasite interactions","volume":"51","author":"CM Ryan","year":"2011","journal-title":"Essays Biochem"},{"issue":"9","key":"ppat.1013216.ref002","doi-asserted-by":"crossref","first-page":"404","DOI":"10.15698\/mic2016.09.526","article-title":"Trichomoniasis - are we giving the deserved attention to the most common non-viral sexually transmitted disease worldwide?","volume":"3","author":"CB Menezes","year":"2016","journal-title":"Microb Cell"},{"issue":"2","key":"ppat.1013216.ref003","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1136\/sti.2003.005124","article-title":"Trichomoniasis: clinical manifestations, diagnosis and management","volume":"80","author":"H Swygard","year":"2004","journal-title":"Sex Transm Infect"},{"key":"ppat.1013216.ref004","doi-asserted-by":"crossref","DOI":"10.1093\/cid\/ciac030","article-title":"Diagnosis and Management of Trichomonas vaginalis: Summary of Evidence Reviewed for the 2021 Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines","volume":"74","author":"PJ Kissinger","year":"2022","journal-title":"Clin Infect Dis"},{"issue":"11","key":"ppat.1013216.ref005","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1128\/EC.4.11.1951-1958.2005","article-title":"Trichomonas vaginalis lipophosphoglycan mutants have reduced adherence and cytotoxicity to human ectocervical cells","volume":"4","author":"FD Bastida-Corcuera","year":"2005","journal-title":"Eukaryot Cell"},{"issue":"4","key":"ppat.1013216.ref006","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1093\/ije\/23.4.682","article-title":"Is Trichomonas vaginalis a cause of cervical neoplasia? 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