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

IMPORTANCE: Inflammasomes are essential for host defense against intracellular bacterial pathogens like Legionella, as they activate caspases, which promote cytokine release and cell death to control infection. In mice, interferon (IFN) signaling promotes inflammasome responses against bacteria by inducing a family of IFN-inducible GTPases known as guanylate-binding proteins (GBPs). Within murine macrophages, IFN promotes the rupture of the Legionella-containing vacuole (LCV), while GBPs are dispensable for this process. Instead, GBPs facilitate the lysis of cytosol-exposed Legionella. In contrast, the functions of IFN and GBPs in human inflammasome responses to Legionella are poorly understood. We show that IFN-γ enhances inflammasome responses to Legionella in human macrophages. Human GBP1 is required for these IFN-γ-driven inflammasome responses. Furthermore, GBP1 co-localizes with Legionella and/or LCVs in a type IV secretion system (T4SS)-dependent manner and promotes damage to the LCV, which leads to increased exposure of the bacteria to the host cell cytosol. Thus, our findings reveal species- and pathogen-specific differences in how GBPs function to promote inflammasome responses.

Effector-triggered immunity and pathogen sensing in metazoans.

Microbial pathogens possess an arsenal of strategies to invade their hosts, evade immune defences and promote infection. In particular, bacteria use virulence factors, such as secreted toxins and effector proteins, to manipulate host cellular processes and establish a replicative niche. Survival of eukaryotic organisms in the face of such challenge requires host mechanisms to detect and counteract these pathogen-specific virulence strategies. In this Review, we focus on effector-triggered immunity (ETI) in metazoan organisms as a mechanism for pathogen sensing and distinguishing pathogenic from non-pathogenic microorganisms. For the purposes of this Review, we adopt the concept of ETI formulated originally in the context of plant pathogens and their hosts, wherein specific host proteins 'guard' central cellular processes and trigger inflammatory responses following pathogen-driven disruption of these processes. While molecular mechanisms of ETI are well-described in plants, our understanding of functionally analogous mechanisms in metazoans is still emerging. In this Review, we present an overview of ETI in metazoans and discuss recently described cellular processes that are guarded by the host. Although all pathogens manipulate host pathways, we focus primarily on bacterial pathogens and highlight pathways of effector-triggered immune defence that sense disruption of core cellular processes by pathogens. Finally, we discuss recent developments in our understanding of how pathogens can evade ETI to overcome these host adaptations.

Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer.

Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers. SIGNIFICANCE: Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.