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

Paul Fineran, Emyr Lloyd-Evans, Nathan A. Lack, Nick Platt, Lianne C. Davis, Anthony J. Morgan, Doris Höglinger, Raju Venkata V. Tatituri, Simon Clark, Ian M. Williams, Patricia Tynan, Nada Al Eisa, Evgeniya Nazarova, Ann Williams, Antony Galione, Daniel S. Ory, Gurdyal S. Besra, David G. Russell, Michael B. Brenner, Edith SimFrances M. Platt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number18
JournalWellcome Open Research
Volume1
DOIs
Publication statusPublished - 2017

Bibliographical note

Funding Information:
Grant information: This work was supported by the Wellcome Trust [202834]; UK Medical Research Council [PF PHD Studentship]; Sport Aiding

Funding Information:
We thank Sarah Spiegel and Sheldon Milstein for commenting on the manuscript, and Lalita Ramakrishnan and Steven Levitte for carrying out the zebrafish studies. We thank Dominic Kelly for assisting with the technical aspects of the Mtb studies. He was unavailable at the time of writing this paper and hence could not be listed as an author. The flow cytometer was funded by the Wellcome Trust (084631).

Funding Information:
Medical Research for Kids (Sparks); Natural Science and Engineering Research Council of Canada [NL PHD Studentship]; King Saud bin Abdulaziz University for Health Sciences [NA PHD Studentship]; Rosetrees Trust [A1263]; European Blaschko Visiting Research Fellowship [DH Post-doctoral Fellowship]; The Royal Society UK [WM130016]; National Institutes of Health [1R21A/102166]. The flow cytometer was funded by the Wellcome Trust (084631).

Funding Information:
This work was supported by the Wellcome Trust [202834]; UK Medical Research Council [PF PHD Studentship]; Sport Aiding Medical Research for Kids (Sparks); Natural Science and Engineering Research Council of Canada [NL PHD Studentship]; King Saud bin Abdulaziz University for Health Sciences [NA PHD Studentship]; Rosetrees Trust [A1263]; European Blaschko Visiting Research Fellowship [DH Post-doctoral Fellowship]; The Royal Society UK [WM130016]; National Institutes of Health [1R21A/102166]. The flow cytometer was funded by the Wellcome Trust (084631).

Publisher Copyright:
© 2017 Fineran P et al.

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