Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration
Berg, Russell D
O’Sullivan, Mary P
O’Leary, Seónadh M
Moens, Cecilia B
Tobin, David M
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Berg, R. D., Levitte, S., O’Sullivan, M. P., O’Leary, S. M., Cambier, C., Cameron, J., Takaki, K., et al. (2016). Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration. Cell, 165 139-152. https://doi.org/10.1016/j.cell.2016.02.034
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 towards 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.
This work was supported by the National Institutes of Health (R37AI054503, LR, R01NS082567, CBM, 5F30HL110455, RB, 1DP2-OD008614, DMT), the Wellcome Trust (LR), the National Institute of Health Research Cambridge Biomedical Research Centre (LR), the Health Research Board of Ireland (HRA_POR/2013/387, MO’S and CSA/2012/16, JK), and The Royal City of Dublin Hospital Trust (Grant 146, JK).
External DOI: https://doi.org/10.1016/j.cell.2016.02.034
This record's URL: https://www.repository.cam.ac.uk/handle/1810/254341
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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