Human Brain Organoid: a new CNSTB model

项目摘要/摘要 中枢神经系统结核是最危险的结核分枝杆菌。 感染。对于这些病例，死亡的风险极高；那些幸存下来的人面临更高的风险。 严重的神经损伤和残疾。尽管它对公共卫生很重要，但目前对它的理解 结核分枝杆菌在大脑中的传播和人脑实质中的抗分枝杆菌免疫是有限的。 这是开发更好的结核病脑膜炎治疗方法的障碍。这种担忧促使美国国家卫生研究院 组织结核病脑膜炎研讨会，为推进中枢神经系统结核病研究制定路线图。工作坊 建立人体体外平台将促进该领域的研究并做出重大贡献 以了解细胞和分子方面对中枢神经系统结核发病机制的洞察。这项提议将检验 并优化了研究中枢神经系统结核分枝杆菌感染的新平台--人脑器官结核分枝杆菌感染。 此前，我们已经发现小鼠大脑中的分枝杆菌感染会导致保护性免疫反应 和细菌控制。虽然有用，但小鼠模型系统并不总是反映人类的许多方面 人类单一和多组分的神经细胞组织的应用将更为合适。 结核分枝杆菌感染吞噬细胞，中枢神经系统感染后脑内的结核分枝杆菌主要分布在募集的单核细胞中 和局部小胶质细胞。我们发现神经前体细胞也可以感染结核杆菌。根据这项提案的 宙斯盾，我们将测试不同的被感染的吞噬细胞如何导致脑结核病。 这项建议的两个主要目标是了解细菌的机制和后果 神经前体细胞摄取(目标1)和应用神经元有机体来测试结核分枝杆菌传播的机制 以及脑细胞对结核分枝杆菌感染的反应。我们建议比较不同结核分枝杆菌感染的吞噬细胞的效果。 在人类神经组织上(目标2和3)。 这项工作的成功完成将使人们对脑结核病的一个新方面有了新的认识 神经前体细胞的感染。这增加了结核分枝杆菌在局部进行神经元替换的可能性。 在那里神经元是结构性产生的。此外，我们还开发了新的人体模型平台来 研究结核分枝杆菌在脑内的传播和对结核分枝杆菌感染的脑特异性反应。

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) of the central nervous system (CNS) is the most dangerous form of M. tuberculosis (Mtb) infection. For these cases, the risk of mortality is extremely high; those who survive are left with an elevated risk of severe neurological damage and disability. Despite its public health importance, current understanding of the dissemination of Mtb in the brain and anti-mycobacterial immunity within the human brain parenchyma is limited. This represents a roadblock for developing a better cure for TB meningitis. This concern motivated the NIH to organize a TB Meningitis workshop to develop a roadmap for advancing CNS TB research. The workshop established that creating human in vitro platforms would facilitate research on the field and significantly contribute to the understanding of cellular and molecular insights into the pathogenesis of CNS TB. This proposal will test and optimize a new platform, Mtb infection of human brain organoids, to study CNS Mtb infection. Previously, we have found that mycobacterial infection of the murine brain leads to protective immune responses and bacterial control. While useful, murine model systems do not always reflect the many aspects of human disease, and the application of human single and multi-component neuronal tissues would be more appropriate. Mtb infects phagocytes, and most of the Mtb in the brain after CNS infection is located in recruited monocytes and local microglia. We discovered that neural progenitors could also be infected with Mtb. Under this proposal's aegis, we will test how the different infected phagocytes contribute to brain tuberculosis. The two main objectives of this proposal are to understand the mechanism and consequences of bacterial uptake by neural progenitors (Aim 1) and to apply neuronal organoids to test mechanisms of Mtb dissemination and brain cell responses to Mtb infection. We propose to compare the effects of different Mtb-infected phagocytes on human neural tissue (Aims 2 and 3). Successful completion of this work will lead to new knowledge on a novel aspect of brain TB concerning neural progenitors' infection. It raises the possibility that Mtb effects neuronal replacement at sites where neurons are constitutively generated. In addition, we develop new human model platforms to study the dissemination of Mtb into the brain and brain-specific responses to Mtb infection.