Guanylate-Binding Protein-Dependent Noncanonical Inflammasome Activation Prevents Burkholderia thailandensis-Induced Multinucleated Giant Cell Formation

摘要

ABSTRACT Inflammasomes are cytosolic multiprotein signaling complexes that are activated upon pattern recognition receptor-mediated recognition of pathogen-derived ligands or endogenous danger signals. Their assembly activates the downstream inflammatory caspase-1 and caspase-4/5 (human) or caspase-11 (mouse), which induces cytokine release and pyroptotic cell death through the cleavage of the pore-forming effector gasdermin D. Pathogen detection by host cells also results in the production and release of interferons (IFNs), which fine-tune inflammasome-mediated responses. IFN-induced guanylate-binding proteins (GBPs) have been shown to control the activation of the noncanonical inflammasome by recruiting caspase-4 on the surface of cytosolic Gram-negative bacteria and promoting its interaction with lipopolysaccharide (LPS). The Gram-negative opportunistic bacterial pathogen Burkholderia thailandensis infects epithelial cells and macrophages and hijacks the host actin polymerization machinery to spread into neighboring cells. This process causes host cell fusion and the formation of so-called multinucleated giant cells (MNGCs). Caspase-1- and IFN-regulated caspase-11-mediated inflammasome pathways play an important protective role against B. thailandensis in mice, but little is known about the role of IFNs and inflammasomes during B. thailandensis infection of human cells, particularly epithelial cells. Here, we report that IFN-γ priming of human epithelial cells restricts B. thailandensis -induced MNGC formation in a GBP1-dependent manner. Mechanistically, GBP1 does not promote bacteriolysis or impair actin-based bacterial motility but acts by inducing caspase-4-dependent pyroptosis of the infected cell. In addition, we show that IFN-γ priming of human primary macrophages confers a more efficient antimicrobial effect through inflammasome activation, further confirming the important role that interferon signaling plays in restricting Burkholderia replication and spread.