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People with CF (pwCF) are often colonized with\n                  <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                  for years to decades, allowing for evolutionary adaptation. In chronic\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  lung isolates from pwCF, the quorum sensing regulator LasR frequently is nonfunctional, however the factors enabling\n                  <jats:italic>lasR<\/jats:italic>\n                  loss-of-function (LOF) mutant selection are incompletely understood. We hypothesized that LOF mutations in\n                  <jats:italic>lasR<\/jats:italic>\n                  could allow\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  to resist the selective pressure of phagocytosis. We found that in multiple strain backgrounds, LasR LOF decreased phagocytosis by both model THP-1 and primary monocyte-derived macrophages. While exogenous administration of the quorum-sensing autoinducer 3-oxo-C12-homoserine-lactone (3OC12HSL) that is made by an enzyme regulated by LasR activity inhibited phagocytosis and mitochondrial respiration, the phagocytosis resistance seen with\n                  <jats:italic>lasR<\/jats:italic>\n                  mutants appears to be bacterial cell intrinsic rather than due to secreted factors. Finally, we found that\n                  <jats:italic>lasR<\/jats:italic>\n                  LOF mutations altered the inflammatory profile upon infection of CF macrophages, with a shift from IL-1 family cytokine expression towards canonical inflammatory markers including IL-6 and TNF\u03b1. Collectively these data provide a potential explanation for both the prevalence of\n                  <jats:italic>lasR<\/jats:italic>\n                  mutants in the CF lung as well as their association with worse outcomes.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    Cystic Fibrosis (CF) is a genetically inherited disease that leads to chronic lung infections.\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    is often implicated with worsening of lung disease, and it evolves in the lung over time to resist eradication. One of the most commonly disrupted gene targets identified in\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    isolates from chronically infected CF lungs is\n                    <jats:italic>lasR<\/jats:italic>\n                    , which encodes a transcription factor which regulates multiple virulence factors. What contributes to the apparent fitness of\n                    <jats:italic>lasR<\/jats:italic>\n                    mutants in the CF lung is not well known. Our study shows that\n                    <jats:italic>lasR<\/jats:italic>\n                    loss-of-function (LOF) mutants resist phagocytosis by macrophages, one of the fundamental mechanisms of clearance by the immune system. We identify mechanisms promoting resistance to phagocytosis, and explore the downstream consequences on inflammatory responses. Understanding why\n                    <jats:italic>lasR<\/jats:italic>\n                    mutations arise could inform strategies to eradicate them from the CF lung and improve outcomes.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.25.678585","type":"posted-content","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T05:10:22Z","timestamp":1758863422000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>Pseudomonas aeruginosa lasR<\/i>\n                  Mutants Resist Phagocytosis and Alter Inflammatory Cytokine Production by Cystic Fibrosis Macrophages"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6132-6472","authenticated-orcid":false,"given":"Daniel S.","family":"Aridgides","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane L.","family":"Mellinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine L.","family":"Gwilt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Hampton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dallas L.","family":"Mould","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah A.","family":"Hogan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix","family":"Ashare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025093001501091000_2025.09.25.678585v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(16)00576-6"},{"key":"2025093001501091000_2025.09.25.678585v2.2","unstructured":"Patient Registry | Cystic Fibrosis Foundation. https:\/\/www.cff.org\/medical-professionals\/patient-registry. 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