title: 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.
authors.affiliation: Molecular & Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Russell D
authors.initials: RD
authors.lastname: Berg
authors.affiliation: Molecular & Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Levitte
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
authors.forename: Mary P
authors.initials: MP
authors.lastname: O'Sullivan
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland.
authors.forename: Seónadh M
authors.initials: SM
authors.lastname: O'Leary
authors.affiliation: Immunology Graduate Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Cambier
authors.affiliation: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: James
authors.initials: J
authors.lastname: Cameron
authors.affiliation: Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Takaki
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Moens
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Tobin
authors.affiliation: Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin 8, Ireland. Electronic address: josephmk@tcd.ie.
authors.forename: Joseph
authors.initials: J
authors.lastname: Keane
authors.affiliation: Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; Department of Microbiology, University of Washington, Seattle, WA 98195, USA. Electronic address: lr404@hermes.cam.ac.uk.
authors.forename: Lalita
authors.initials: L
authors.lastname: Ramakrishnan
mesh_terms: D000818:Animals; D004198:Disease Susceptibility; D006099:Granuloma / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000276:immunology; D009164:Mycobacterium Infections / Q000276:immunology* / Q000473:pathology*; D019910:Mycobacterium marinum; D011650:Pulmonary Alveoli / Q000276:immunology; D012907:Smoking; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology / Q000473:pathology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C093069:SNAPC1 protein, human; C000609921:Snapc1b protein, zebrafish; D014157:Transcription Factors; D029961:Zebrafish Proteins