Harding Alfred T, Gehrke Lee, Vyas Jatin M, Harding Hannah Brown
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
J Fungi (Basel). 2025 Jul 19;11(7):539. doi: 10.3390/jof11070539.
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 . 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 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.
随着免疫功能低下个体以及患有免疫相关合并症（如新冠肺炎）的患者数量增加，真菌感染率正在上升。这种增长，再加上目前抗真菌药物研发处于停滞状态，使得了解这些病原体的发病机制和传播情况比以往任何时候都更加重要。真菌感染的小鼠模型虽然在基础科学层面提供了信息，但在转化为人类疾病方面存在严重局限性。在此，我们展示的数据支持采用人类脑类器官模型来研究真菌感染及向中枢神经系统（CNS）的传播，该模型由人类胚胎干细胞生成，能准确重现相关脑细胞类型和结构。这种方法为在体内模型无法实现的情况下，直接洞察特定真菌病原体在人体组织中的相关发病机制提供了途径。利用这个模型系统，我们评估了已知能穿越血脑屏障（BBB）的真菌病原体（如 ）对大脑的特异性嗜性和细胞效应。我们确定了这种真菌病原体对这些模型类器官的整体大体形态、细胞结构和细胞因子释放的影响。此外，我们证明了 能穿透并侵入类器官组织，且在感染全过程中持续存在。这些结果证明了这个新模型在该领域的实用性，并突出了该系统在阐明真菌发病机制以开发预防和治疗隐球菌性脑膜炎等真菌疾病播散阶段的新治疗策略方面的潜力。
