Human GBP1 Differentially Targets Salmonella and Toxoplasma to License Recognition of Microbial Ligands and Caspase-Mediated Death

Interferon-inducible Guanylate binding proteins (GBPs) promote cell-intrinsic defense through host cell death. GBPs target pathogens and pathogen-containing vacuoles, and assist in membrane-disruption for release of microbial molecules that trigger inflammasome activation. GBP1 mediates atypical macrophage apoptosis or pyroptosis infected with Toxoplasma gondii or Salmonella Typhimurium, respectively. The pathogen-proximal detection-mechanisms of GBP1 are poorly understood, since humans lack functional Immunity-related GTPases (IRGs) which control mGbps in mice. Here, we describe two new assays showing that GBP1 promotes lysis of Tg-containing vacuoles and parasite plasma membranes, releasing Tg-DNA. In contrast, we show GBP1 targets cytosolic STm, recruits caspase-4 to the bacterial surface for its activation by LPS but does not contribute to bacterial vacuole escape. During STm infection, caspase-1 cleaves and inactivates GBP1, and expression of cleavage-deficient GBP1D192E mutant increased pyroptosis through absence of feedback inhibition. Our studies elucidate microbe-specific roles of GBP1 in infection-detection triggering assembly of divergent caspase signaling platforms.