Role of Mycobacterium leprae proteins and RNAs in initiating neuropathy

周围神经病变是一个主要的全球健康问题，影响着数百万人，他们有感觉和运动功能丧失的临床症状，并由疾病状况、衰老、损伤或感染引起。感染性神经病的一个典型例子是麻风神经病，它主要是由麻风分枝杆菌（ML）感染雪旺细胞、神经胶质细胞或成人PNS轴突的支持细胞引起的。由于ML独特地感染成人雪旺细胞，并在极长潜伏期后逐渐引起人类神经病变，因此这种细菌感染提供了一个很好的模型，可以描述由于感染而改变的雪旺细胞如何促进轴突变性和感觉和运动神经元脱髓鞘的开始。最近，我们发现ML劫持了成年雪旺细胞的显著可塑性，并在先天免疫因子激活之前将感染细胞重编程为祖细胞/干细胞样细胞。在本项目中，我们提出在雪旺细胞内由ML蛋白和ML rna产生的免疫因子可以直接影响周围或周围的神经，招募炎症细胞，导致感觉和运动神经损伤的开始。同样，我们还提出，表皮感觉神经末梢的损伤是由于ML感染的表皮角化细胞释放免疫因子所致，与雪旺细胞无关。因此，我们计划在组织培养模型和斑马鱼模型中鉴定具有诱导先天免疫基因/因子能力的ML候选蛋白和rna，并确定其在轴突变性中的作用，该模型已被很好地表征为研究活体动物的神经变性过程。基于这些结果，我们将选择最有希望的候选ML蛋白和rna，并生成转基因小鼠模型，这些模型可能概括ML如何自然启动轴突变性导致神经性疾病。我们预计，从这个模型中获得的知识最终将允许我们测试具有减轻轴突变性和脱髓鞘能力的小分子药物，从而开发新的治疗方法来阻止麻风病神经病变的神经变性，并且可能对其他神经性疾病和疾病也有影响。

Peripheral neuropathy is a major global health problem affecting millions of people with clinical symptoms of sensory and motor function loss, and results from disease conditions, aging, injury or infection. A classic example of infectious neuropathies is leprosy neuropathy, which is caused primarily by Mycobacterium leprae (ML) infection of the Schwann cells, the glial cells or supporting cells for the axons of the adult PNS. Since ML uniquely infect adult Schwann cells and progressively causes neuropathic conditions in humans after extremely long incubation period, this bacterial infection provides an excellent model to delineate how altered Schwann cells, as a result of infection, contribute to the initiation of the axonal degeneration and demyelination of sensory and motor neurons. Recently, we discovered that ML hijacks the notable plasticity of adult Schwann cells and reprograms infected cells to progenitor/stem cell-like cells that precedes the activation of innate immune factors. In this project, we propose that Immune factors generated within Schwann cells by ML proteins and ML RNAs can directly affect the enclosing or surrounding nerves and recruite inflammatory cells, leading to the initiation of sensory and motor nerve damage. Similarly, we also propose that the damage to sensory nerve endings in the epidermis is due to release of immune factors from ML infected epidermal keratinocytes, independent of Schwann cell involvement. Thus, we plan to identify candidate ML proteins and RNAs with the capacity to elicit innate immune genes/factors and determine their role in axonal degeneration in tissue culture models and zebrafish model, which has been well characterized to study neurodegeneration process in living animals. Based on these results we will select most promising candidate ML proteins and RNAs and generate transgenic mouse models, which are likely to recapitulate how ML naturally initiates axonal degeneration leading to neuropathic conditions. We anticipate that the knowledge gain from this model will eventually permit us to test small molecule drugs with the ability to alleviate axonal degeneration and demyelination, and thus develop new therapeutics to halt nervedegeneration in leprosy neuropathy, and may also have implications for other neuropathic conditions and diseases.