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: 6688330
• 负责人: ANURA RAMBUKKANA
• 金额: $ 39.66万
• 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/6688330
• 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。麻风分枝杆菌感染三叉神经节的神经胶质细胞雪旺细胞是麻风神经损害的主要原因。我们最近发现，非髓鞘雪旺细胞，而不是有髓雪旺细胞，优先容纳麻风杆菌，因此是持续感染的细胞内生态位。由于麻风杆菌是一种专性的细胞内病原体，其倍增时间最长，基因组中的基因数量有限，因此在非髓鞘雪旺细胞内建立生产性感染是细菌生存的关键。然而，麻风杆菌在雪旺细胞内存活的机制尚不清楚。针对麻风杆菌的生存策略将为开发新的治疗方法对抗神经损伤和疾病进展提供理性。为了研究这些方面，我们使用原代人雪旺细胞(从人类周围神经分离和纯化)作为模型，因为它们在体内的表型类似于无髓雪旺细胞。细胞内麻风杆菌在体外可维持数周的活性，不会对雪旺细胞造成任何细胞凋亡或细胞病变效应。使用Affymetrix Human GeneChips和从原代人雪旺细胞中制备的cRNA进行微阵列分析，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/抑制因子，(Iii)生长/神经营养因子，(Iv)生长因子受体，以及(V)相关的转录和信号分子。因此，我们认为，麻风杆菌一旦被感染，一方面有效地利用雪旺细胞机制维持细菌的活性，另一方面通过调节雪旺细胞的生长来确保细菌长期存活的细胞内生态位。为此，我们将研究以下几个方面：(1)麻风杆菌对雪旺细胞代谢/分解代谢功能的调节；(2)麻风杆菌对人雪旺细胞周期的调控；(3)麻风杆菌诱导的生长/神经营养因子及其对雪旺细胞信号、生长和功能的影响。这些研究将为PNS中持续的麻风支原体感染、麻风患者的神经损伤以及神经胶质细胞的基本生物学提供新的见解。