Role of Mycobacterium leprae proteins and RNAs in initiating neuropathy

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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.