Human Brain Organoid: a new CNSTB model

项目总结/摘要 中枢神经系统（CNS）的结核病（TB）是最危险的M。结核病（Mtb） 感染对于这些病例，死亡风险极高;幸存者的风险也会升高 严重的神经损伤和残疾尽管其对公共卫生的重要性，目前对 Mtb在脑中的传播和人脑实质内的抗分枝杆菌免疫是有限的。 这是开发更好的结核性脑膜炎治疗方法的一个障碍。这种担忧促使NIH 组织结核性脑膜炎研讨会，制定推进中枢神经系统结核病研究的路线图。讲习班 建立人类体外平台将促进该领域的研究， 对中枢神经系统结核病发病机制的细胞和分子见解的理解。该提案将测试 并优化了一个新的研究中枢神经系统结核分枝杆菌感染的平台--人脑类器官结核分枝杆菌感染。 以前，我们已经发现，分枝杆菌感染的小鼠大脑导致保护性免疫反应 和细菌控制。虽然有用，但鼠模型系统并不总是反映人模型系统的许多方面。 疾病，和人类单一和多组分神经元组织的应用将是更合适的。 Mtb感染吞噬细胞，CNS感染后脑内的Mtb大多位于募集的单核细胞中 和局部小胶质细胞。我们发现神经祖细胞也可以感染结核分枝杆菌。根据这项提议， Aegis，我们将测试不同的感染吞噬细胞如何导致脑结核。 该提案的两个主要目标是了解细菌感染的机制和后果。 通过神经祖细胞的摄取（Aim 1）和应用神经元类器官来测试Mtb传播的机制 和脑细胞对结核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影响， 对人类神经组织的作用（目标2和3）。 这项工作的成功完成将导致对脑结核病的一个新方面的新知识， 神经前体细胞感染。它提出了结核分枝杆菌影响神经元替代的可能性， 神经元在那里组成性地产生。此外，我们还开发新的人体模型平台， 研究结核分枝杆菌向大脑的传播和大脑对结核分枝杆菌感染的特异性反应。

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.