{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T20:45:59Z","timestamp":1787863559416,"version":"build-2784847793"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2025,2,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              <jats:italic>Cryptococcus neoformans<\/jats:italic>\n              is a fungal pathogen that can cause lethal disease in immunocompromised patients. Immunocompetent host immune responses, such as formation of pulmonary granulomas, control the infection and prevent disseminated disease. Little is known about the immunological conditions establishing the latent infection granuloma in the lungs. To investigate this, we performed an analysis of pulmonary immune cell populations, cytokine changes, and granuloma formation during infection with a latent disease-causing clinical isolate in C3HeB\/FeJ mice over 360 days. We found that latently infected mice progress through three phases of granuloma formation where different immune profiles dominate: an early phase characterized by eosinophilia, high IL-4\/IL-13, and\n              <jats:italic>C. neoformans<\/jats:italic>\n              proliferation in the lungs; an intermediate phase characterized by multinucleated giant cell formation, high IL-1\u03b1\/IFN\u03b3, granuloma expansion, and increased blood antigen levels; and a late phase characterized by a significant expansion of T cells, granuloma condensation, and decreases in lung fungal burden and blood antigen levels. These findings highlight a complex series of immune changes that occur during the establishment of granulomas that control\n              <jats:italic>C. neoformans<\/jats:italic>\n              in the lungs and lay the foundation for studies to identify critical beneficial immune responses to\n              <jats:italic>Cryptococcus<\/jats:italic>\n              infections.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                <jats:italic>Cryptococcus neoformans<\/jats:italic>\n                is a fungal pathogen that disseminates from the lungs to the brain to cause fatal disease. Latent C.\n                <jats:italic>neoformans<\/jats:italic>\n                infection in the lungs is controlled by organized collections of immune cells called granulomas. The formation and structure of\n                <jats:italic>Cryptococcus<\/jats:italic>\n                granulomas are poorly understood due to inconsistent human pathology results and disagreement between necrotic granuloma-forming rat models and non-necrotic granuloma-forming mouse models. To overcome this, we investigated granuloma formation during latent\n                <jats:italic>C. neoformans<\/jats:italic>\n                infection in the C3HeB\/FeJ mouse strain which forms necrotic lung granulomas in response to other pathogens. We found that latent\n                <jats:italic>C. neoformans<\/jats:italic>\n                granuloma formation progresses through phases that we described as early, intermediate, and late with different immune response profiles and granulomatous characteristics. Ultimately, we show that C3HeB\/FeJ mice latently infected with\n                <jats:italic>C. neoformans<\/jats:italic>\n                form non-necrotic granulomas and could provide a novel mouse model to investigate host immune response profiles.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.03610-24","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T14:02:04Z","timestamp":1736863324000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["Pulmonary granuloma formation during latent\n            <i>Cryptococcus neoformans<\/i>\n            infection in C3HeB\/FeJ mice involves progression through three immunological phases"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0364-4816","authenticated-orcid":true,"given":"Jovany J.","family":"Betancourt","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Marina","family":"Yoder","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]},{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech","place":["Blacksburg, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issa","family":"Mutyaba","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah M.","family":"Atkins","sequence":"additional","affiliation":[{"name":"Division of Comparative Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill","place":["Chapel Hill, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"De la Cruz","sequence":"additional","affiliation":[{"name":"Pathology Services Core, University of North Carolina Chapel Hill","place":["Chapel Hill, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Meya","sequence":"additional","affiliation":[{"name":"College of Health Sciences, Makerere University","place":["Kampala, Uganda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2318-168X","authenticated-orcid":true,"given":"Kirsten","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota","place":["Minneapolis, USA"]},{"name":"Department of Biomedical Sciences and Pathobiology, Virginia Tech","place":["Blacksburg, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009342"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(22)00499-6"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.175.6.1685"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.804059"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0046-8177(85)80060-5"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10156-005-0387-x"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/25.1.14"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/20.3.611"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012513-104653"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00046-19"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01905-15"},{"key":"e_1_3_4_13_2","first-page":"123","volume-title":"Current topics in microbiology and immunology","author":"Kramnik I","year":"2008","unstructured":"Kramnik I. 2008. 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