Human GBP1 promotes pathogen vacuole rupture and inflammasome activation during Legionella pneumophila infection

The inflammasome is an essential component of host defense against intracellular bacterial pathogens, such as Legionella pneumophila, the causative agent of the severe pneumonia Legionnaires disease. Inflammasome activation leads to recruitment and activation of caspases, which promote IL-1 family cytokine release and pyroptosis. In mice, interferon (IFN) signaling promotes inflammasome responses against L. pneumophila, in part through the functions of a family of IFN-inducible GTPases known as guanylate binding proteins (GBPs) (1). Within murine macrophages, IFN signaling promotes rupture of the L. pneumophila-containing vacuole (LCV), whereas GBPs are dispensable for vacuole rupture. Instead, GBPs facilitate the lysis of cytosol-exposed L. pneumophila. In contrast to mouse GBPs, the functions of human GBPs in inflammasome responses to L. pneumophila are poorly understood. Here, we show that IFN-{gamma} promotes caspase-1, caspase-4, and caspase-5 inflammasome activation during L. pneumophila infection and upregulates GBP expression in primary human macrophages. We find that human GBP1 is important for maximal IFN-{gamma}-driven inflammasome responses to L. pneumophila. Furthermore, IFN-{gamma} signaling promotes the rupture of LCVs. Intriguingly, in contrast to murine GBPs, human GBP1 targets the LCV in a T4SS-dependent manner and promotes vacuolar lysis, resulting in increased bacterial access to the host cell cytosol. Our findings show a key role for human GBP1 in targeting and disrupting pathogen-containing vacuoles and reveal mechanistic differences in how mouse and human GBPs promote inflammasome responses to L. pneumophila.