Cell
Volume 165, Issue 1, 24 March 2016, Pages 139-152
Journal home page for Cell

Article
Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

https://doi.org/10.1016/j.cell.2016.02.034Get rights and content
Under a Creative Commons license
open access

Highlights

  • Lysosomal storage diseases reduce macrophage endocytic recycling and migration

  • Reduced macrophage migration increases tuberculosis severity via granuloma breakdown

  • Tobacco smoke particles accumulate in lysosomes of smokers’ alveolar macrophages

  • Lysosomal particles reduce smokers’ macrophage migration to infecting mycobacteria

Summary

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.

Cited by (0)

9

Co-first author

10

Present address: Department of Chemistry, Stanford University, Stanford, CA 94305, USA

11

Present address: Environmental and Fisheries Science Division, National Oceanic and Atmospheric Administration, Seattle, WA 98115, USA