Human GBP1 facilitates the rupture of the Legionella-containing vacuole and inflammasome activation

The inflammasome is essential for host defense against intracellular bacterial pathogens, including Legionella pneumophila, the causative agent of the severe pneumonia Legionnaires' disease. Inflammasomes recruit and activate caspases, which promote IL-1 family cytokine release and pyroptosis to restrict infection. In mice, interferon (IFN) signaling promotes inflammasome responses against L. pneumophila and other bacteria, in part, through inducing a family of IFN-inducible GTPases known as guanylate-binding proteins (GBPs). Within murine macrophages, IFN promotes the rupture of the L. pneumophila-containing vacuole (LCV), while GBPs are dispensable for vacuole rupture. Instead, GBPs facilitate the lysis of cytosol-exposed L. pneumophila. In contrast, the functions of IFN-gamma and GBPs in human inflammasome responses to L. pneumophila are poorly understood. Here, we show that IFN-gamma enhances caspase-1- and caspase-4-dependent inflammasome responses to L. pneumophila in human macrophages. We find that human GBP1 is required for these IFN-gamma-driven inflammasome responses. Furthermore, we find that GBP1 co-localizes with L. pneumophila and/or LCVs in a type IV secretion system (T4SS)-dependent manner and facilitates damage to the LCV, resulting in increased bacterial access to the host cell cytosol. Our findings reveal species- and pathogen-specific differences in how GBPs function during infection.

Automated summary

The inflammasome is critical for the host defense against intracellular bacterial pathogens. IFN and GBP1 play important roles in the inflammasome response to Legionella pneumophila infection in human macrophages, enhancing cytokine release and facilitating bacterial access to the host cell cytosol.