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Cell. 2016 Mar 24;165(1):139-152. doi: 10.1016/j.cell.2016.02.034.

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration.

Author information

1
Molecular & Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA.
2
Molecular & Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
3
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
4
Immunology Graduate Program, University of Washington, Seattle, WA 98195, USA.
5
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
6
Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
7
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
8
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA.
9
Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland. Electronic address: josephmk@tcd.ie.
10
Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; Department of Microbiology, University of Washington, Seattle, WA 98195, USA. Electronic address: lr404@hermes.cam.ac.uk.

Abstract

A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis.

PMID:
27015311
PMCID:
PMC4819607
DOI:
10.1016/j.cell.2016.02.034
[Indexed for MEDLINE]
Free PMC Article

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