Abstract
Organelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogen Salmonella led us to discover that type I IFN (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I signaling modified the localization, acidification, protease activity, and proteomic profile of lysosomes. Proteomic and genetic analyses revealed that multiple IFN-I-stimulated genes including IFITM3, SLC15A3, and CNP contribute to lysosome acidification. IFN-I-dependent lysosome acidification was associated with elevated intracellular Salmonella virulence gene expression, rupture of the Salmonella-containing vacuole, and host cell death. Moreover, IFN-I signaling promoted in vivo Salmonella pathogenesis in the intestinal epithelium where Salmonella initiates infection, indicating that IFN-I signaling can modify innate defense in the epithelial compartment. We propose that IFN-I control of lysosome function broadly impacts host defense against diverse viral and microbial pathogens.
Keywords:
Salmonella pathogenesis; intestinal epithelium; lysosome; mucosal defense; type I interferon.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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CRISPR-Cas Systems / genetics
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Disease Models, Animal
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Epithelial Cells / chemistry
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Epithelial Cells / cytology
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Epithelial Cells / immunology*
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Epithelial Cells / metabolism
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Gene Expression Regulation, Bacterial / immunology
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HT29 Cells
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Host-Pathogen Interactions / genetics
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Host-Pathogen Interactions / immunology
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Humans
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Hydrogen-Ion Concentration
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Immunity, Innate
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Interferon Type I / metabolism*
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Intestinal Mucosa / cytology
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / microbiology
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Lysosomes / chemistry
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Lysosomes / immunology
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Lysosomes / metabolism*
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Mice
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Mice, Knockout
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Necroptosis / immunology
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Peptide Hydrolases / metabolism
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Proteomics
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Receptor, Interferon alpha-beta / genetics
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Receptor, Interferon alpha-beta / metabolism
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Salmonella Infections / immunology*
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Salmonella Infections / microbiology
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Salmonella typhimurium / immunology
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Salmonella typhimurium / pathogenicity
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Signal Transduction / immunology
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Virulence / immunology
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Virulence Factors / genetics
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Virulence Factors / metabolism
Substances
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Bacterial Proteins
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Ifnar1 protein, mouse
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Interferon Type I
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Virulence Factors
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Receptor, Interferon alpha-beta
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Peptide Hydrolases