{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T08:42:41Z","timestamp":1768725761500,"version":"3.49.0"},"reference-count":77,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T00:00:00Z","timestamp":1658275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Stanford Maternal and Child Health Research Institute (MCHRI) Postdoctoral Award FY2019","award":["1R01HL157414-01"],"award-info":[{"award-number":["1R01HL157414-01"]}]},{"name":"Stanford Maternal and Child Health Research Institute (MCHRI) Postdoctoral Award FY2019","award":["1K08HL122528-01A1"],"award-info":[{"award-number":["1K08HL122528-01A1"]}]},{"name":"the National Institutes of Health, National Heart Lung and Blood Institute","award":["1R01HL157414-01"],"award-info":[{"award-number":["1R01HL157414-01"]}]},{"name":"the National Institutes of Health, National Heart Lung and Blood Institute","award":["1K08HL122528-01A1"],"award-info":[{"award-number":["1K08HL122528-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Cystic fibrosis (CF) lung transplant recipients (LTRs) exhibit a disproportionately high rate of life-threatening invasive aspergillosis (IA). Loss of the cystic fibrosis transmembrane conductance regulator (CFTR-\/-) in macrophages (m\u03c6s) has been associated with lyosomal alkalinization. We hypothesize that this alkalinization would persist in the iron-laden post-transplant microenvironment increasing the risk of IA. To investigate our hypothesis, we developed a murine CF orthotopic tracheal transplant (OTT) model. Iron levels were detected by immunofluorescence staining and colorimetric assays. Aspergillus fumigatus (Af) invasion was evaluated by Grocott methenamine silver staining. Phagocytosis and killing of Af conidia were examined by flow cytometry and confocal microscopy. pH and lysosomal acidification were measured by LysoSensorTM and LysotrackerTM, respectively. Af was more invasive in the CF airway transplant recipient compared to the WT recipient (p &lt; 0.05). CFTR-\/- m\u03c6s were alkaline at baseline, a characteristic that was increased with iron-overload. These CFTR-\/- m\u03c6s were unable to phagocytose and kill Af conidia (p &lt; 0.001). Poly(lactic-co-glycolic acid) (PLGA) nanoparticles acidified lysosomes, restoring the CFTR-\/- m\u03c6s\u2019 ability to clear conidia. Our results suggest that CFTR-\/- m\u03c6s\u2019 alkalinization interacts with the iron-loaded transplant microenvironment, decreasing the CF-m\u03c6s\u2019 ability to kill Af conidia, which may explain the increased risk of IA. Therapeutic pH modulation after transplantation could decrease the risk of IA.<\/jats:p>","DOI":"10.3390\/jof8070751","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T11:22:24Z","timestamp":1658316144000},"page":"751","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Macrophage Lysosomal Alkalinization Drives Invasive Aspergillosis in a Mouse Cystic Fibrosis Model of Airway Transplantation"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0907-0203","authenticated-orcid":false,"given":"Efthymia Iliana","family":"Matthaiou","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6992-3020","authenticated-orcid":false,"given":"Wayland","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA"},{"name":"Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5202-2998","authenticated-orcid":false,"given":"Carol","family":"Conrad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Pulmonary Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joe","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA 94304, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"165rv13","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden Killers: Human Fungal Infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. 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