{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T15:55:41Z","timestamp":1784908541019,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Fungal communities in the gut influence host immunity, yet most studies have focused on cell wall components rather than genetic materials. Here, we explore how fungal genomic DNA (gDNA) from Candida albicans, Saccharomyces cerevisiae, and Cryptococcus neoformans modulate immune responses in human CD4+ T cells, murine splenocytes, and THP-1-derived macrophages. We find that C. albicans gDNA promotes the development of regulatory T cells and increases IL-10, fostering immune tolerance and preserving CD4+ T cell viability in an inflammatory setting. S. cerevisiae gDNA induces moderate Treg responses with restrained effector T cell expansion and higher checkpoint gene expression, entirely consistent with its commensal nature. In contrast, C. neoformans gDNA elicits a strongly inflammatory profile, promoting Th1\/Th17 cells and driving high cytokine production. Mechanistically, C. albicans and S. cerevisiae gDNA dampen DNA-sensing pathways and enhance immune checkpoint molecules that act as brakes against overactivation, while C. neoformans gDNA robustly activates innate sensing pathways with limited checkpoint induction. These species-specific signaling profiles reveal that fungal gDNA itself can influence whether the immune system adopts a tolerant or inflammatory response toward fungi. This discovery highlights fungal genomic DNA as a previously underappreciated regulator of host\u2013fungus interactions, offering new insight into commensal persistence, pathogenic invasion, and the potential for DNA-based antifungal interventions.<\/jats:p>","DOI":"10.3390\/jof11110760","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T05:20:44Z","timestamp":1761196844000},"page":"760","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Divergent Immunomodulatory Roles of Fungal DNA in Shaping Treg and Inflammatory Responses"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3272-2513","authenticated-orcid":false,"given":"Dongmei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idalia","family":"Cruz","sequence":"additional","affiliation":[{"name":"Department of Oncology, Animal Models, Shared Resources, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4512-830X","authenticated-orcid":false,"given":"Yahui","family":"Feng","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Mycology, Jining No. 1 People\u2019s Hospital, Jining 272067, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Moussa","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Digvijay","family":"Patil","sequence":"additional","affiliation":[{"name":"MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kroemer","sequence":"additional","affiliation":[{"name":"MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5038-7202","authenticated-orcid":false,"given":"Joseph A.","family":"Bellanti","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Georgetown University Medical Center, Washington, DC 20057, USA"},{"name":"Department of Pediatrics, Georgetown University Medical Center, Washington, DC 20057, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/j.1462-5822.2005.00659.x","article-title":"Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms","volume":"8","author":"Urban","year":"2006","journal-title":"Cell Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"myae008","DOI":"10.1093\/mmy\/myae008","article-title":"Neutrophil extracellular traps (NETs) and Th-2 dominant immune responses in chronic granulomatous chromoblastomycosis","volume":"62","author":"Huang","year":"2024","journal-title":"Med. 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