Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

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...

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Main Authors:	Berg, Russell D., Levitte, Steven, O’Sullivan, Mary P., O’Leary, Seónadh M., Cambier, C.J., Cameron, James, Takaki, Kevin K., Moens, Cecilia B., Tobin, David M., Keane, Joseph, Ramakrishnan, Lalita
Format:	Online
Language:	English
Published:	Cell Press 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819607/

id	pubmed-4819607
recordtype	oai_dc
spelling	pubmed-48196072016-04-14 Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration Berg, Russell D. Levitte, Steven O’Sullivan, Mary P. O’Leary, Seónadh M. Cambier, C.J. Cameron, James Takaki, Kevin K. Moens, Cecilia B. Tobin, David M. Keane, Joseph Ramakrishnan, Lalita 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. Cell Press 2016-03-24 /pmc/articles/PMC4819607/ /pubmed/27015311 http://dx.doi.org/10.1016/j.cell.2016.02.034 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Berg, Russell D. Levitte, Steven O’Sullivan, Mary P. O’Leary, Seónadh M. Cambier, C.J. Cameron, James Takaki, Kevin K. Moens, Cecilia B. Tobin, David M. Keane, Joseph Ramakrishnan, Lalita
spellingShingle	Berg, Russell D. Levitte, Steven O’Sullivan, Mary P. O’Leary, Seónadh M. Cambier, C.J. Cameron, James Takaki, Kevin K. Moens, Cecilia B. Tobin, David M. Keane, Joseph Ramakrishnan, Lalita Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration
author_facet	Berg, Russell D. Levitte, Steven O’Sullivan, Mary P. O’Leary, Seónadh M. Cambier, C.J. Cameron, James Takaki, Kevin K. Moens, Cecilia B. Tobin, David M. Keane, Joseph Ramakrishnan, Lalita
author_sort	Berg, Russell D.
title	Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration
title_short	Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration
title_full	Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration
title_fullStr	Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration
title_full_unstemmed	Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration
title_sort	lysosomal disorders drive susceptibility to tuberculosis by compromising macrophage migration
description	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.
publisher	Cell Press
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819607/
_version_	1613561710431436800

Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

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