Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration.
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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.
Published Version (Please cite this version)10.1016/j.cell.2016.02.034
Publication InfoBerg, Russell D; Levitte, Steven; O'Sullivan, Mary P; O'Leary, Seónadh M; Cambier, CJ; Cameron, James; ... Ramakrishnan, Lalita (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.
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Associate Professor of Molecular Genetics and Microbiology
Tuberculosis: Mycobacterial Pathogenesis and Host Susceptibility Tuberculosis kills 1.5 million people annually. Our laboratory aims to understand the intricate interplay between mycobacteria and their hosts using a combination of model organism genetics, human genetics, pharmacology and high-resolution microscopy. By identifying key pathways utilized by the infecting bacteria and the host innate immune system, we hope to discover new therapeutic targets and interventi