Targeting M. Leprae survival strategies in the PNS

针对 PNS 中的麻风分枝杆菌生存策略

• 批准号: 6987893
• 负责人: ANURA RAMBUKKANA
• 金额: $ 38.73万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987893
• 关键词: Targeting; M.; Leprae; survival; strategies

DESCRIPTION (provided by applicant): Leprosy remains an important global health problem, and represents a classical example of infectious neuro-degenerative diseases of the peripheral nervous system (PNS). Mycobacterium leprae infection of the Schwann cell, the glial cell of the PNS, is the primary cause for the nerve damage in leprosy. We have recently shown that the non-myelinating Schwann cell, but not the myelinated Schwann cell, preferentially harbors M. leprae, and thus serves as the intracellular niche for persistent infection. Because M. leprae is an obligate intra-cellular pathogen with the longest doubling time and a limited number of genes in its genome, the establishment of productive infection within non-myelinated Schwann cells is the key for bacterial survival. However, the mechanisms of M. leprae survival within Schwann cells are unknown. Targeting of M. leprae survival strategies will provide the rational to develop new therapeutics to combat the neurological injury and disease progression. To study these aspects, we used primary human Schwann cells (isolated and purified from human peripheral nerves) as a model, since they phenotypically resemble non-myelinated Schwann cells in vivo. Intracellular M. leprae in vitro maintain viability for several weeks without causing any apoptosis or cytopathic effect to Schwann cells. Microarray analysis using Affymetrix human GeneChips with cRNA prepared from primary human Schwann cells infected with viable M. leprae for 30 days, we showed that the majority of differentially expressed Schwann cells genes are (i) enzymes that regulate metabolic and respiratory functions, (ii) cell cycle regulators/inhibitors, (iii) growth/neurotropic factors, (iv) growth factor receptors and (v) associated transcriptional and signaling molecules. Therefore, we propose that once infected, M. leprae effectively use Schwann cell machinery on one hand to maintain the bacterial viability and the other hand to secure the intracellular niche for long-term bacterial survival by regulating Schwann cell growth. To study these, we will study the following: (1) M. leprae regulation of Schwann cell metabolic/catabolic functions, (2) Regulation of human Schwann cell cycle by M. leprae, and (3) M. leprae-induced growth/neurotropic factors and their effects on Schwann cell signaling, growth and functions. These studies should provide novel insight into the persistent M. leprae infection in the PNS, nerve damage in leprosy patients, and the basic biology of glial cells.

描述（由申请人提供）：麻风病仍然是一个重要的全球健康问题，是周围神经系统（PNS）传染性神经退行性疾病的典型例子。麻风分枝杆菌感染的雪旺细胞，神经胶质细胞的PNS，是麻风病的神经损害的主要原因。我们最近发现，无髓鞘的雪旺细胞，而不是有髓鞘的雪旺细胞，优先窝藏M。麻风，并因此作为持续感染的细胞内生态位。因为M.麻风病是一种专性细胞内病原体，倍增时间最长，其基因组中基因数量有限，在无髓鞘施万细胞内建立生产性感染是细菌生存的关键。然而，M.麻风病人在雪旺氏细胞中存活率是未知的。M的目标。麻风生存策略将为开发新的治疗方法以对抗神经损伤和疾病进展提供理论依据。为了研究这些方面，我们使用原代人许旺细胞（从人外周神经分离和纯化）作为模型，因为它们在表型上类似于体内的无髓鞘许旺细胞。胞内M.麻风在体外维持存活数周而不引起任何细胞凋亡或对雪旺细胞的细胞病变效应。微阵列分析使用具有cRNA的Affyssin人基因芯片，所述cRNA从用活的M.麻风30天后，我们发现大多数差异表达的雪旺细胞基因是（i）调节代谢和呼吸功能的酶，（ii）细胞周期调节剂/抑制剂，（iii）生长/神经营养因子，（iv）生长因子受体和（v）相关的转录和信号分子。因此，我们建议，一旦感染，M。麻风病有效地利用许旺细胞机制，一方面维持细菌活力，另一方面通过调节许旺细胞生长来确保细胞内生态位以供细菌长期存活。为了研究这些现象，我们将研究以下几个方面：（1）M.麻风对雪旺细胞代谢/分解代谢功能的调节;（2）麻风杆菌对雪旺细胞周期的调节。（3）M.麻风诱导的生长/神经营养因子及其对雪旺细胞信号传导、生长和功能的影响。这些研究将为持续性M。PNS中的麻风感染、麻风患者的神经损伤和胶质细胞的基本生物学。