Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Berg, RD; Levitte, S; O'Sullivan, MP; O'Leary, SM; Cambier, CJ; Cameron, J; Takaki, KK; Moens, CB; Tobin, DM; Keane, J; Ramakrishnan, L

Published Date

  • March 2016

Published In

Volume / Issue

  • 165 / 1

Start / End Page

  • 139 - 152

PubMed ID

  • 27015311

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2016.02.034

Language

  • eng