{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:47:55Z","timestamp":1792205275035,"version":"4.4.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Pseudomonas aeruginosa<\/jats:italic> is a major opportunistic pathogen that causes chronic infections, particularly in patients with cystic fibrosis and chronic obstructive pulmonary disease (COPD). The type VI secretion system (T6SS) is a primary virulence factor of <jats:italic>P. aeruginosa<\/jats:italic> in chronic infections. The objective of this study was to elucidate the regulatory mechanisms and pathogenic effects of the T6SS during <jats:italic>P. aeruginosa<\/jats:italic> infection, utilizing transcriptome sequencing and functional assays. We found that T6SS expression is elevated in <jats:italic>P. aeruginosa<\/jats:italic> isolated from chronically infected patients. Deletion of the <jats:italic>retS<\/jats:italic> gene activates <jats:italic>P. aeruginosa<\/jats:italic> PAO1 T6SS while repressing T3SS <jats:italic>in vitro<\/jats:italic>. Bacterial and cellular transcriptome sequencing analyses showed that T6SS genes were upregulated, while T3SS genes were downregulated in the \u0394<jats:italic>retS<\/jats:italic> mutant. Additionally, the expression levels of the fimbriae gene <jats:italic>cupC<\/jats:italic>, the histidine phosphotransfer protein <jats:italic>hptC<\/jats:italic> (<jats:italic>PA0033<\/jats:italic>), and the transcription factor <jats:italic>PA0034<\/jats:italic> were significantly increased. Subsequent experiments revealed that adhesion mediated by <jats:italic>cupC<\/jats:italic> enhances the contact-killing activity of the T6SS. Deletion of the <jats:italic>hptC<\/jats:italic>-<jats:italic>PA0034<\/jats:italic> operon results in the down-regulation of <jats:italic>cupC<\/jats:italic> expression. The \u0394<jats:italic>retS<\/jats:italic>\u0394<jats:italic>cupC<\/jats:italic> and \u0394<jats:italic>retS<\/jats:italic>\u0394<jats:italic>hptC<\/jats:italic>-<jats:italic>PA0034<\/jats:italic> mutants exhibited reduced cytotoxicity compared to the \u0394<jats:italic>retS<\/jats:italic> mutant, similar to the \u0394<jats:italic>retS<\/jats:italic>\u0394<jats:italic>clpV1<\/jats:italic>\u0394<jats:italic>clpV2<\/jats:italic> mutant. The \u0394<jats:italic>retS<\/jats:italic> infection increased cell death, inflammatory factors (IL-1\u03b2, IL-6, TNF-\u03b1), and reactive oxygen species compared to a T6SS-inactive strain. Importantly, our study demonstrates that the T6SS activates the PDE4C pathway in epithelial cells, leading to significant cellular alterations. The application of PDE inhibitors effectively mitigates cell damage and inflammatory responses. These findings highlight the critical role of T6SS in modulating host cell signaling and suggest potential therapeutic strategies for conditions associated with T6SS-mediated inflammation.<\/jats:p>","DOI":"10.3389\/fcimb.2025.1582339","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T08:44:15Z","timestamp":1749545055000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Transcriptomic profiling reveals RetS-mediated regulation of type VI secretion system and host cell responses in Pseudomonas aeruginosa infections"],"prefix":"10.3389","volume":"15","author":[{"given":"Yinglin","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangcheng","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shebin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haining","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieying","family":"Pu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cha","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1093\/nar\/gkab1254","article-title":"RpoN\/Sfa2-dependent activation of the Pseudomonas aeruginosa H2-T6SS and its cognate arsenal of antibacterial toxins","volume":"50","author":"Allsopp","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"7707","DOI":"10.1073\/pnas.1700286114","article-title":"RsmA and AmrZ orchestrate the assembly of all three type VI secretion systems in Pseudomonas aeruginosa","volume":"114","author":"Allsopp","year":"2017","journal-title":"Proc. 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