{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T14:46:26Z","timestamp":1787409986057,"version":"build-2736575974"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017170","name":"Thailand Science Research and Innovation","doi-asserted-by":"crossref","award":["Fundamental Fund fiscal year 2024, Thammasat University"],"award-info":[{"award-number":["Fundamental Fund fiscal year 2024, Thammasat University"]}],"id":[{"id":"10.13039\/501100017170","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Alveolar macrophages are well known as the first responders to pulmonary cryptococcosis; however, their dynamic molecular responses to <jats:italic><jats:italic>Cryptococcus gattii<\/jats:italic><\/jats:italic> infection in vivo remain limited. Here, we investigated the transcriptional profiles of lung alveolar macrophages purified from mice intranasally infected with <jats:italic><jats:italic>C. gattii<\/jats:italic><\/jats:italic> and compared them to those infected with <jats:italic><jats:italic>C. neoformans<\/jats:italic><\/jats:italic> using RNA sequencing analysis. Alveolar macrophages from <jats:italic><jats:italic>C. gattii<\/jats:italic><\/jats:italic>-infected mice exhibited distinct transcriptional alterations, particularly in genes associated with sterol biosynthesis, whereas those from <jats:italic><jats:italic>C. neoformans<\/jats:italic><\/jats:italic>-infected mice showed enrichment in interferon and cytokine signaling pathways. Treatment with the sterol biosynthesis inhibitor lovastatin significantly reduced cholesterol accumulation in <jats:italic><jats:italic>C. gattii-<\/jats:italic><\/jats:italic>infected RAW 264.7 cells. Furthermore, lovastatin treatment of <jats:italic><jats:italic>C. gattii<\/jats:italic><\/jats:italic>-infected RAW 264.7 and bone marrow-derived macrophages suppressed intracellular cryptococcal proliferation and augmented inflammatory response, as evidenced by increased expression of <jats:italic><jats:italic>Nos2<\/jats:italic><\/jats:italic> and <jats:italic><jats:italic>Il6<\/jats:italic><\/jats:italic>. Lovastatin also potentiated the antifungal effect of fluconazole by promoting intracellular fungal clearance and increasing nitric oxide activity in macrophages. In <jats:italic><jats:italic>C. gattii<\/jats:italic><\/jats:italic>-infected mice, lovastatin treatment enhanced the efficacy of fluconazole, resulting in improved pulmonary fungal clearance, increased lung CD4\u2009\u207a\u2009T cell numbers, and elevated nitric oxide activity. Collectively, these findings reveal a unique macrophage response to <jats:italic><jats:italic>C. gattii<\/jats:italic><\/jats:italic> infection and highlight the role of sterol metabolism in modulating host defense, offering potential avenues for therapeutic intervention.<\/jats:p>","DOI":"10.1371\/journal.pone.0333090","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T17:24:32Z","timestamp":1759253072000},"page":"e0333090","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Transcriptomic profiling of lung alveolar macrophages reveals distinct contribution of sterol metabolism in macrophage response to Cryptococcus gattii infection"],"prefix":"10.1371","volume":"20","author":[{"given":"Siranart","family":"Jeerawattanawart","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adithap","family":"Hansakon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi","family":"Alberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongliang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0303-9544","authenticated-orcid":true,"given":"Pornpimon","family":"Angkasekwinai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"pone.0333090.ref001","unstructured":"Organization WH. 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