Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.635239
Title: Pathogenic mycobacteria achieve cellular persistence via lipid-mediated inhibition of the Niemann-Pick disease type C pathway
Author: Fineran, Paul David
ISNI:       0000 0004 5354 9339
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2014
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Abstract:
M.tuberculosis, the causative agent of human tuberculosis, is able to achieve long-term persistence within host organism macrophages. This persistence is achieved via the ability of the mycobacterium to prevent phagosomal-lysosomal fusion. The mechanisms by which fusion is inhibited remain incompletely understood. Here we provide evidence supporting a mechanistic link between infection with pathogenic mycobacteria and the cellular pathway defective in the rare lysosomal storage disorder Niemann-Pick disease type C (NPC). We observed that NPC phenotypes, including lipid storage and reduced lysosomal calcium release, can be induced in wild-type murine and human macrophages by infection with pathogenic mycobacteria. This phenotype induction did not occur following infection with the non-pathogenic M.smegmatis. Phenotype induction could be achieved in the absence of the mycobacteria using lipids from the mycobacterial cell walls. The importance of mycobacterial cell wall lipids to mycobacterial virulence has been well-documented. This lipid-mediated inhibition likely occurs through the NPC1 protein. Susceptibility to phenotype induction was inversely proportional to levels of functional NPC1, whilst a pre-existing dysfunction in the NPC pathway (either stemming from mutation or pharmacological inhibition) rendered cells less able to clear non-pathogenic mycobacteria. Finally, we demonstrate that therapies for NPC, particularly curcumin, are able to promote clearance of mycobacteria from infected macrophages. NPC therapies may hold promise for a new approach to the treatment of tuberculosis.
Supervisor: Platt, Frances Mary Sponsor: Medical Research Council ; National Institute of Health
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.635239  DOI: Not available
Keywords: Life Sciences ; Microbiology ; Medical Sciences ; Infectious diseases ; Pharmacology
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