Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.

Autor:	Fineran P; Department of Pharmacology, University of Oxford, Oxford, UK., Lloyd-Evans E; Department of Pharmacology, University of Oxford, Oxford, UK.; School of Biosciences, Cardiff University, Cardiff, UK., Lack NA; Department of Pharmacology, University of Oxford, Oxford, UK.; School of Medicine, Koç University, Istanbul, Turkey., Platt N; Department of Pharmacology, University of Oxford, Oxford, UK., Davis LC; Department of Pharmacology, University of Oxford, Oxford, UK., Morgan AJ; Department of Pharmacology, University of Oxford, Oxford, UK., Höglinger D; Department of Pharmacology, University of Oxford, Oxford, UK., Tatituri RVV; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA., Clark S; Public Health England, Salisbury, UK., Williams IM; Department of Pharmacology, University of Oxford, Oxford, UK., Tynan P; Department of Pharmacology, University of Oxford, Oxford, UK., Al Eisa N; Department of Pharmacology, University of Oxford, Oxford, UK., Nazarova E; Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, USA., Williams A; Public Health England, Salisbury, UK., Galione A; Department of Pharmacology, University of Oxford, Oxford, UK., Ory DS; Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, USA., Besra GS; School of Biosciences, University of Birmingham, Birmingham, UK., Russell DG; Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, USA., Brenner MB; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA., Sim E; Department of Pharmacology, University of Oxford, Oxford, UK.; Faculty of Science Engineering and Computing, Kingston University, Kingston upon Thames, UK., Platt FM; Department of Pharmacology, University of Oxford, Oxford, UK.
Jazyk:	angličtina
Zdroj:	Wellcome open research [Wellcome Open Res] 2016 Nov 18; Vol. 1, pp. 18. Date of Electronic Publication: 2016 Nov 18.
DOI:	10.12688/wellcomeopenres.10036.2
Abstrakt:	Background: Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis , achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with persistent mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC), a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC. Methods: The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed. Results: Macrophages infected with persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca 2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca 2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in promoting clearance of mycobacteria from infected host cells. Conclusion: These findings provide a novel mechanistic explanation for mycobacterial intracellular persistence, and suggest that targeting interactions between the mycobacteria and host cell pathways may provide a novel avenue for development of anti-TB therapies. Competing Interests: FMP is a Royal Society Wolfson Research Merit Award holder and a Wellcome Trust Investigator in Science. FP is a consultant for Actelion (miglustat). FP and AG are co-founders of IntraBio Inc. No other authors have a conflict of interest.
Databáze:	MEDLINE
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