Functional remodeling of lysosomes by type I interferon modifies host defense

The degradative activity of lysosomes is essential for cellular homeostasis and also functions in innate defense against intracellular microbes. Pathogens commonly modify lysosome and other organelle functions to promote virulence, but host factors that stimulate organelle re-modeling remain largely uncharacterized. Here, a CRISPR/Cas9 screen in intestinal epithelial cells with Salmonella , a prototypical intracellular bacterial pathogen, led us to discover that type I interferon (IFN-I) governs lysosome function. IFN-I signaling modified the localization, acidification, protease activity and proteomic profile of lysosomes, amplifying intracellular Salmonella virulence gene expression and host cell death. IFN-I promoted in vivo Salmonella pathogenesis not only in bone marrow-derived cells, but also in the intestinal epithelium, where Salmonella initiates infection. Our findings explain how a bacterial pathogen co-opts epithelial IFN-I signaling, and unveil an unexpected role for IFN-I signaling in control of lysosomal function. We propose that immune signal-induced organelle remodeling at barrier surfaces may broadly impact host defense against diverse infectious agents.