MYCOBACTERIUM LEPRAE ANTIGENS AND NERVE DAMAGE

麻风分枝杆菌抗原与神经损伤

• 批准号: 6374223
• 负责人: ANURA RAMBUKKANA
• 金额: $ 23.93万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374223
• 关键词: Mycobacterium leprae; Schwann cells; bacteria infection mechanism; bacterial antigens; binding proteins; glycolipids; laminin; molecular cloning; molecular pathology; myelinopathy; nerve injury; plasmids; protein binding; tissue /cell culture

DESCRIPTION (Adapted from the Applicant's Abstract): Mycobacterium leprae is unique among bacterial pathogens in its ability to invade the peripheral nervous system and to cause nerve damage, which accounts for the disabilities in leprosy patients. This property makes M. leprae a model to study the mechanism of nerve damage, particularly demyelination, in other neurodegenerative diseases. The components of M. leprae which bind peripheral nerves and induce nerve damage are not known. The PI proposes that M. leprae interferes with critical Schwann cell functions and subsequently causes nerve dysfunction before the immune response comes into play. Using a well-characterized in vitro Schwann cell-sensory neuron co-culture system, which mimics in vivo conditions, but is devoid of immune cells, the PI found that M. leprae and its cell wall fraction alone induce significant demyelination and axonal damage. The PI and colleagues have recently shown that laminin-2 is an initial neural target of M. leprae; since the laminin-2 isoform completely surrounds the Schwann cell-axon units, the PI proposes that M. leprae should bind to laminin-2 before inducing nerve damage in early infection. Therefore, laminin-2-binding antigens are the most likely components of M. leprae that mediate bacterial binding and invasion, and also induce nerve damage. The main theme of the application is to systematically identify the laminin-binding components of M. leprae that mediate the initial interaction with peripheral nerves and characterize their capacity to induce nerve damage. In preliminary studies, the PI has shown that phenolic glycolipid 1 (PGL-1) and a novel M. leprae cell wall protein of 21 kDa bind laminin-2. These data also suggest the presence of other laminin-binding components of M. leprae. Since the preliminary studies indicate that PGL-1 alone can induce significant demyelination, the PI proposes that the laminin-binding components are capable of inducing demyelination. Therefore, the PI proposes the following: (1) characterize the laminin-2-binding activity of PGL-1 and the 21 kDa protein and their roles in Schwann cell invasion, (2) identify and characterize other potential laminin-binding components in the M. leprae genome with special emphasis on M. leprae-specific proteins by screening an ordered cosmid library of M. leprae, using laminin-2 as a probe, and (3) characterize the demyelination and axonal damage induced by M. leprae laminin-binding components. These studies should provide important insights into the early molecular events of nerve damage in leprosy and other neurodegenerative diseases and will eventually lead to the development of novel therapeutics and diagnostics for peripheral neuropathies.

描述(摘自申请者摘要)：麻风分枝杆菌 在细菌病原体中独一无二的是它入侵外周的能力 神经系统和导致神经损伤，这是导致残疾的原因 在麻风病患者身上。这一特性使麻风杆菌成为研究 神经损伤的机制，特别是脱髓鞘 神经退行性疾病。麻风杆菌结合外周的成分 神经和诱导神经损伤是未知的。公安部建议麻风杆菌 干扰关键的雪旺细胞功能，随后导致神经 在免疫反应开始发挥作用之前就会出现功能障碍。使用 在体外雪旺细胞-感觉神经元共培养系统中， PI发现，它模仿体内的情况，但缺乏免疫细胞 单单麻风杆菌及其细胞壁组分就能显著地 脱髓鞘和轴突损伤。PI和他的同事们最近证明 层粘连蛋白-2是麻风杆菌的初始神经靶标；由于层粘连蛋白-2亚型 完全围绕雪旺细胞-轴突单位，PI提出M。 麻风在早期引起神经损伤前应与层粘连蛋白-2结合 感染。因此，层粘连蛋白-2结合抗原是最有可能的成分 麻风杆菌的一种，介导细菌的结合和入侵，并诱导神经 损坏。该应用程序的主要主题是系统地识别 介导初始相互作用的麻风杆菌层粘连蛋白结合组分 与周围神经的关系，并描述其导致神经损伤的能力。 在初步研究中，PI表明酚醛糖脂1(PGL-1)和 一种新的21 kDa的麻风杆菌细胞壁蛋白结合层粘连蛋白-2。这些数据还 提示麻风杆菌存在其他层粘连蛋白结合成分。自.以来 初步研究表明，仅PGL-1就可以诱导显著的 脱髓鞘，PI提出层粘连蛋白结合成分能够 会导致脱髓鞘。因此，PI提出了以下建议：(1) 鉴定PGL-1与21 kDa蛋白的层粘连蛋白-2结合活性 它们在雪旺细胞侵袭中的作用，(2)识别和表征其他 麻风杆菌基因组中潜在的层粘连蛋白结合组分 通过筛选有序粘粒文库重点研究麻风杆菌特异性蛋白 用层粘连蛋白-2作为探针，以及(3)表征了麻风杆菌 麻风杆菌层粘连蛋白结合引起的脱髓鞘和轴突损伤 组件。这些研究应该会为早期的 麻风和其他神经退行性变患者神经损伤的分子事件 疾病，并最终将导致新的疗法和 周围神经病诊断学。