The Role of Schwann Cell Lipid Droplets In Neuropathology of Leprosy

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Summary Leprosy is no longer designated as a global health problem by the WHO (defined by a registered prevalence of less than one case of leprosy per 10,000 population); however, about 200,000 new cases are still reported each year. Recently several epidemiological reports based on “find-and-treat” campaigns have indicated under reporting and suggested “hidden-leprosy”. This, as well as the identification of environmental reservoirs, would explain the continued transmission of the etiological agent, Mycobacterium leprae, in the human population. The most pronounced forms of this disease manifest with sever deformities and physical disabilities that are a result of irreversible nerve damage caused by the pathogen's tropism for peripheral nerves. Specifically, M. leprae has evolved and adapted to infect and survive in Schwann cells (SCs), where defined host-pathogen interactions result in demyelination and nerve fibrosis. The molecular and biochemical interactions of M. leprae and SCs have not been well defined. Thus, elucidating these interactions and their downstream consequences is essential to understand the neuropathogenesis of leprosy and to develop appropriate interventions. The ability of M. leprae to induce lipid droplet formation in SCs has been established as key and fundamental aspect of M. leprae pathogenicity. As such, the focus of the proposed research is to define the molecular interactions that result in lipid droplet formation by M. leprae infected SCs and understand how M. leprae utilizes lipids from these droplets to support its growth and drive pathogenesis. These objectives are based on the unifying hypothesis that, via surface ligands M. leprae gains access to SCs and induces lipid droplet formation. The pathogen modulation of host cell lipid metabolism promotes SC dysfunction and the generation of a permissive innate immune response that facilitates bacilli persistence in the nerve. Further, M. leprae catabolism of the lipid droplet associated cholesterol supports the pathogens intracellular growth, as well as drives cell signaling events that result in impairment of myelin production and stability.