Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration.

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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1016/j.cell.2016.02.034

Publication Info

Berg, Russell D, Steven Levitte, Mary P O'Sullivan, Seónadh M O'Leary, CJ Cambier, James Cameron, Kevin K Takaki, Cecilia B Moens, et al. (2016). Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration. Cell, 165(1). pp. 139–152. 10.1016/j.cell.2016.02.034 Retrieved from https://hdl.handle.net/10161/12374.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.