Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration

Summary

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.

Graphical Abstract

Highlights

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  Lysosomal storage diseases reduce macrophage endocytic recycling and migration

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  Reduced macrophage migration increases tuberculosis severity via granuloma breakdown

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  Tobacco smoke particles accumulate in lysosomes of smokers’ alveolar macrophages

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  Lysosomal particles reduce smokers’ macrophage migration to infecting mycobacteria

Abstract

Lysosomal dysfunction caused by genetic mutations or accumulation of tobacco particulates in the lysosomal compartment impairs macrophage function and formation of stable tuberculous granulomas, providing a possible explanation for the increased susceptibility to tuberculosis in smokers.