{"doi":"10.1128/mbio.01707-23","title":"Human GBP1 facilitates the rupture of the <i>Legionella-</i> containing vacuole and inflammasome activation","abstract":"ABSTRACT 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-γ and GBPs in human inflammasome responses to L. pneumophila are poorly understood. Here, we show that IFN-γ 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-γ-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. 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.","journal":"mBio","year":2023,"id":333466,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":854642,"name":"Marisa S. Egan","orcid":"0000-0001-6191-5552","position":1,"is_corresponding":false},{"id":402291,"name":"Jasmine Alexander-Floyd","orcid":"0000-0003-1894-0060","position":2,"is_corresponding":false},{"id":985566,"name":"Natasha Lopes Fischer","orcid":"0000-0002-8836-8365","position":3,"is_corresponding":false},{"id":1060818,"name":"Jessica Doerner","orcid":"0000-0002-1569-5955","position":4,"is_corresponding":false},{"id":299108,"name":"Sunny Shin","orcid":"0000-0001-5214-9577","position":5,"is_corresponding":false},{"id":570219,"name":"Antonia R Bass","orcid":"0000-0002-5623-0572","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T01:09:39.719497Z","pmid":"37737612","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}