Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases
ABSTRACT Cryptococcus neoformans 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 conditi...
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American Society for Microbiology
2025-02-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03610-24 |
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| author | Jovany J. Betancourt Minna Ding J. Marina Yoder Issa Mutyaba Hannah M. Atkins Gabriela De la Cruz David B. Meya Kirsten Nielsen |
| author_facet | Jovany J. Betancourt Minna Ding J. Marina Yoder Issa Mutyaba Hannah M. Atkins Gabriela De la Cruz David B. Meya Kirsten Nielsen |
| author_sort | Jovany J. Betancourt |
| collection | DOAJ |
| description | ABSTRACT Cryptococcus neoformans 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 C. neoformans proliferation in the lungs; an intermediate phase characterized by multinucleated giant cell formation, high IL-1α/IFNγ, 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 C. neoformans in the lungs and lay the foundation for studies to identify critical beneficial immune responses to Cryptococcus infections.IMPORTANCECryptococcus neoformans is a fungal pathogen that disseminates from the lungs to the brain to cause fatal disease. Latent C. neoformans infection in the lungs is controlled by organized collections of immune cells called granulomas. The formation and structure of Cryptococcus 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 C. neoformans infection in the C3HeB/FeJ mouse strain which forms necrotic lung granulomas in response to other pathogens. We found that latent C. neoformans 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 C. neoformans form non-necrotic granulomas and could provide a novel mouse model to investigate host immune response profiles. |
| format | Article |
| id | doaj-art-133bc93e9f194686bf0af402262a2022 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-133bc93e9f194686bf0af402262a20222025-02-05T14:00:48ZengAmerican Society for MicrobiologymBio2150-75112025-02-0116210.1128/mbio.03610-24Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phasesJovany J. Betancourt0Minna Ding1J. Marina Yoder2Issa Mutyaba3Hannah M. Atkins4Gabriela De la Cruz5David B. Meya6Kirsten Nielsen7Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USADivision of Comparative Medicine, Department of Pathology and Laboratory Medicine, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USAPathology Services Core, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USACollege of Health Sciences, Makerere University, Kampala, UgandaDepartment of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, USAABSTRACT Cryptococcus neoformans 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 C. neoformans proliferation in the lungs; an intermediate phase characterized by multinucleated giant cell formation, high IL-1α/IFNγ, 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 C. neoformans in the lungs and lay the foundation for studies to identify critical beneficial immune responses to Cryptococcus infections.IMPORTANCECryptococcus neoformans is a fungal pathogen that disseminates from the lungs to the brain to cause fatal disease. Latent C. neoformans infection in the lungs is controlled by organized collections of immune cells called granulomas. The formation and structure of Cryptococcus 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 C. neoformans infection in the C3HeB/FeJ mouse strain which forms necrotic lung granulomas in response to other pathogens. We found that latent C. neoformans 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 C. neoformans form non-necrotic granulomas and could provide a novel mouse model to investigate host immune response profiles.https://journals.asm.org/doi/10.1128/mbio.03610-24Cryptococcus neoformansgranulomalatent infectioncryptococcosisC3HeB/FeJadaptive immunity |
| spellingShingle | Jovany J. Betancourt Minna Ding J. Marina Yoder Issa Mutyaba Hannah M. Atkins Gabriela De la Cruz David B. Meya Kirsten Nielsen Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases mBio Cryptococcus neoformans granuloma latent infection cryptococcosis C3HeB/FeJ adaptive immunity |
| title | Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases |
| title_full | Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases |
| title_fullStr | Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases |
| title_full_unstemmed | Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases |
| title_short | Pulmonary granuloma formation during latent Cryptococcus neoformans infection in C3HeB/FeJ mice involves progression through three immunological phases |
| title_sort | pulmonary granuloma formation during latent cryptococcus neoformans infection in c3heb fej mice involves progression through three immunological phases |
| topic | Cryptococcus neoformans granuloma latent infection cryptococcosis C3HeB/FeJ adaptive immunity |
| url | https://journals.asm.org/doi/10.1128/mbio.03610-24 |
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