Targetting the Niemann-Pick disease type C cellular pathway as a novel approach t

University Of Oxford, Oxford

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Abstract

DESCRIPTION (provided by applicant): Pathogenic mycobacteria such as Mycobacteria tuberculosis (Mtb) target host cellular pathways in order to survive and persist long-term within the endocytic system of host macrophages. This represents an important therapeutic target for this disease, for which there are currently limited options. We have been studying a rare human genetic disease, Niemann-Pick disease type C (NPC), which is characterised at the cellular level by the storage of multiple lipid species including cholesterol, reduced acidic store calcium levels, and a block in late endosome: lysosome fusion. We have been struck by the presence of multiple convergent features to the cellular pathology of Mtb infected cells and NPC disease cells. For example, both become lipid laden with cholesterol and have a block in phagosome: lysosome fusion. We speculated that this could indicate mechanistic convergence and that Mtb may shed lipids that inhibit the NPC cell biological pathway. This would prevent fusion with the lysosome by reducing acidic store calcium levels, which would in turn prevent the mycobacteria from being cleared. Here, we present a substantial body of preliminary data demonstrating that Mtb and BCG do shed lipids that inhibit the NPC cellular pathway. In murine tissue culture model small molecule therapies that we and others have developed for treating NPC disease, efficacy in clearing mycobacteria from infected cells is demonstrated by targeting host cell pathways that correct or compensate for dysfunction of the NPC pathway. In this application we will test approved therapeutics in human macrophage culture systems, and mouse infection models of Mtb. In addition, we will identify the biochemical nature of the shed lipids, and determine how they inhibit the function of the NPC pathway.