Human Brain Organoids: A New Model to Study <i>Cryptococcus neoformans</i> Neurotropism
With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these o...
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MDPI AG
2025-07-01
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| Series: | Journal of Fungi |
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| Online Access: | https://www.mdpi.com/2309-608X/11/7/539 |
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| author | Alfred T. Harding Lee Gehrke Jatin M. Vyas Hannah Brown Harding |
| author_facet | Alfred T. Harding Lee Gehrke Jatin M. Vyas Hannah Brown Harding |
| author_sort | Alfred T. Harding |
| collection | DOAJ |
| description | With the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic scientific level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood–brain barrier (BBB), such as <i>Cryptococcus neoformans</i>. We determined the effects of this fungal pathogen on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that <i>C. neoformans</i> penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to develop new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis. |
| format | Article |
| id | doaj-art-9f909fd9aa564b0d9a646a99f1d32bd2 |
| institution | DOAJ |
| issn | 2309-608X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Fungi |
| spelling | doaj-art-9f909fd9aa564b0d9a646a99f1d32bd22025-08-20T02:45:56ZengMDPI AGJournal of Fungi2309-608X2025-07-0111753910.3390/jof11070539Human Brain Organoids: A New Model to Study <i>Cryptococcus neoformans</i> NeurotropismAlfred T. Harding0Lee Gehrke1Jatin M. Vyas2Hannah Brown Harding3Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USAInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USADivision of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USADivision of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USAWith the rise in immunocompromised individuals and patients with immune-related comorbidities such as COVID-19, the rate of fungal infections is growing. This increase, along with the current plateau in antifungal drug development, has made understanding the pathogenesis and dissemination of these organisms more pertinent than ever. The mouse model of fungal infection, while informative on a basic scientific level, has severe limitations in terms of translation to the human disease. Here we present data supporting the implementation of the human cerebral organoid model, which is generated from human embryonic stem cells and accurately recapitulates relevant brain cell types and structures, to study fungal infection and dissemination to the central nervous system (CNS). This approach provides direct insight into the relevant pathogenesis of specific fungal organisms in human tissues where in vivo models are impossible. With this model system we assessed the specific brain tropisms and cellular effects of fungal pathogens known to cross the blood–brain barrier (BBB), such as <i>Cryptococcus neoformans</i>. We determined the effects of this fungal pathogen on the overall gross morphology, cellular architecture, and cytokine release from these model organoids. Furthermore, we demonstrated that <i>C. neoformans</i> penetrates and invades the organoid tissue and remains present throughout the course of infection. These results demonstrate the utility of this new model to the field and highlight the potential for this system to elucidate fungal pathogenesis to develop new therapeutic strategies to prevent and treat the disseminated stages of fungal diseases such as cryptococcal meningitis.https://www.mdpi.com/2309-608X/11/7/539cerebral organoidfungal pathogenmodel system<i>Cryptococcus neoformans</i> |
| spellingShingle | Alfred T. Harding Lee Gehrke Jatin M. Vyas Hannah Brown Harding Human Brain Organoids: A New Model to Study <i>Cryptococcus neoformans</i> Neurotropism Journal of Fungi cerebral organoid fungal pathogen model system <i>Cryptococcus neoformans</i> |
| title | Human Brain Organoids: A New Model to Study <i>Cryptococcus neoformans</i> Neurotropism |
| title_full | Human Brain Organoids: A New Model to Study <i>Cryptococcus neoformans</i> Neurotropism |
| title_fullStr | Human Brain Organoids: A New Model to Study <i>Cryptococcus neoformans</i> Neurotropism |
| title_full_unstemmed | Human Brain Organoids: A New Model to Study <i>Cryptococcus neoformans</i> Neurotropism |
| title_short | Human Brain Organoids: A New Model to Study <i>Cryptococcus neoformans</i> Neurotropism |
| title_sort | human brain organoids a new model to study i cryptococcus neoformans i neurotropism |
| topic | cerebral organoid fungal pathogen model system <i>Cryptococcus neoformans</i> |
| url | https://www.mdpi.com/2309-608X/11/7/539 |
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