The Role of Schwann Cell Lipid Droplets In Neuropathology of Leprosy

摘要 麻风病不再被世界卫生组织指定为全球健康问题(定义为 每10,000人中不到1例麻风病例)；然而，每个人仍报告约200,000例新病例 年。最近，几份基于“发现和治疗”运动的流行病学报告表明，在 报告和建议的“隐匿型麻风”。这一点，以及识别环境水库，将 解释麻风分枝杆菌在人类人群中的持续传播。这个 这种疾病最明显的表现形式是严重的畸形和身体残疾 由于病原体对周围神经的趋向性而造成的不可逆转的神经损伤。具体来说，麻风杆菌有 进化并适应于在雪旺细胞(SCs)中感染和生存，其中定义了宿主与病原体的相互作用 导致脱髓鞘和神经纤维化。麻风杆菌与干细胞的分子和生化相互作用 还没有得到很好的定义。因此，阐明这些相互作用及其下游后果至关重要。 了解麻风的神经发病机制，并制定相应的干预措施。麻风杆菌的能力 在干细胞中诱导脂滴形成已被确定为麻风杆菌的关键和基础方面 致病性。因此，拟议研究的重点是定义导致以下结果的分子相互作用 麻风杆菌感染的干细胞形成脂滴并了解麻风杆菌如何利用这些液滴中的脂类 以支持其生长和驱动其发病机制。这些目标基于统一的假设，即通过 麻风杆菌表面配体可与干细胞结合，诱导脂滴形成。青枯病病原菌的调控 宿主细胞脂质代谢促进SC功能障碍和产生允许性先天免疫反应 这有助于细菌在神经中的持久力。此外，麻风杆菌对相关脂滴的分解代谢 胆固醇支持病原体在细胞内的生长，并驱动细胞信号事件，导致 髓鞘生成和稳定性受损。

Summary Leprosy is no longer designated as a global health problem by the WHO (defined by a registered prevalence of less than one case of leprosy per 10,000 population); however, about 200,000 new cases are still reported each year. Recently several epidemiological reports based on “find-and-treat” campaigns have indicated under reporting and suggested “hidden-leprosy”. This, as well as the identification of environmental reservoirs, would explain the continued transmission of the etiological agent, Mycobacterium leprae, in the human population. The most pronounced forms of this disease manifest with sever deformities and physical disabilities that are a result of irreversible nerve damage caused by the pathogen's tropism for peripheral nerves. Specifically, M. leprae has evolved and adapted to infect and survive in Schwann cells (SCs), where defined host-pathogen interactions result in demyelination and nerve fibrosis. The molecular and biochemical interactions of M. leprae and SCs have not been well defined. Thus, elucidating these interactions and their downstream consequences is essential to understand the neuropathogenesis of leprosy and to develop appropriate interventions. The ability of M. leprae to induce lipid droplet formation in SCs has been established as key and fundamental aspect of M. leprae pathogenicity. As such, the focus of the proposed research is to define the molecular interactions that result in lipid droplet formation by M. leprae infected SCs and understand how M. leprae utilizes lipids from these droplets to support its growth and drive pathogenesis. These objectives are based on the unifying hypothesis that, via surface ligands M. leprae gains access to SCs and induces lipid droplet formation. The pathogen modulation of host cell lipid metabolism promotes SC dysfunction and the generation of a permissive innate immune response that facilitates bacilli persistence in the nerve. Further, M. leprae catabolism of the lipid droplet associated cholesterol supports the pathogens intracellular growth, as well as drives cell signaling events that result in impairment of myelin production and stability.