Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway
| Autor: | Simon Clark, Anthony J. Morgan, Raju V. V. Tatituri, Emyr Lloyd-Evans, Lianne C. Davis, Frances M. Platt, Edith Sim, Nick Platt, David G. Russell, Doris Höglinger, Nathan A. Lack, Evgeniya V. Nazarova, Ann Williams, Paul Fineran, Nada Al Eisa, Patricia W. Tynan, Gurdyal S. Besra, Daniel S. Ory, Antony Galione, Ian M. Williams, Michael B. Brenner |
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| Přispěvatelé: | Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Fineran, Paul, Lloyd-Evans, Emyr, Platt, Nick, Davis, Lianne C., Morgan, Anthony J., Höglinger, Doris, Tatituri, Raju Venkata Veera, Clark, Simon O., Williams, Ian M., Tynan, Patricia W., Eisa, Nada Al, Nazarova, Evgeniya V., Williams, Ann I.O., Galione, Antony G., Ory, Daniel S., Besra, Gurdyal Singh, Russell, David G., Brenner, Michael B., Sim, Edith, Platt, Frances M., School of Medicine, Department of Pharmacology |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Programmed cell death Endocytic cycle Cell Medicine (miscellaneous) Tuberculosis Niemann-pick Disease Type C Lysosomal Storage Diseases Lysosomal calcium Bioinformatics General Biochemistry Genetics and Molecular Biology Niemann-Pick Disease Type C 03 medical and health sciences 0302 clinical medicine Lysosome Lysosomal storage disease Genetics of the Immune System Medicine Pharmacology Niemann–Pick disease type C business.industry Articles medicine.disease Cell biology 3. Good health medicine.anatomical_structure 030104 developmental biology Respiratory Infections NPC1 Lysosomal Calcium business Intracellular 030217 neurology & neurosurgery Research Article |
| Zdroj: | Turkish Journal of Urology Wellcome Open Research |
| ISSN: | 2398-502X |
| Popis: | 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 intracellular 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 intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca2+ 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 intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca2+ 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. Wellcome Trust; National Institutes of Health; Natural Sciences and Engineering Research Council of Canada; Rosetrees Trust; Research Councils UK |
| Databáze: | OpenAIRE |
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