{"doi":"10.1101/2025.07.18.665318","title":"Early Antibody-Mediated Immunity to Tuberculosis in Mice Requires NLRP3","abstract":"(Mtb), their mechanisms of action remain incompletely understood. Here, we demonstrate that immune complexes of Mtb and monoclonal antibodies targeting the Mtb phosphate transporter subunit PstS1 robustly activate the NLRP3 inflammasome in human and murine macrophages, leading to enhanced interleukin-1β secretion. Surprisingly, antibody-mediated inflammasome activation occurred independently of cell-surface Fcγ receptors, as confirmed using Fc-domain glycosylation mutant mAbs and macrophages from Fcγ receptor-deficient mice. Crucially, NLRP3 is indispensable for early antibody-mediated protection in vivo, as both pharmacological inhibition, and genetic deletion of NLRP3 completely abolished protective effects of PstS1-specific antibodies in Mtb-infected mice. This mechanism extends beyond monoclonal antibodies, as polyclonal sera from intravenously BCG-immunized rhesus macaques also required NLRP3 for protective efficacy. Our findings reveal a previously unrecognized mechanism by which Mtb-specific antibodies enhance host defense through inflammasome activation, potentially informing novel approaches for tuberculosis vaccine development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555690,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1038234,"name":"Nyaradzai Sithole","orcid":"0000-0002-8020-223X","position":1,"is_corresponding":false},{"id":1454951,"name":"Avia Watson","orcid":null,"position":2,"is_corresponding":false},{"id":1454505,"name":"Lilach Abramovitz","orcid":"0000-0001-9961-9986","position":3,"is_corresponding":false},{"id":1454952,"name":"Katya Rakayev","orcid":null,"position":4,"is_corresponding":false},{"id":1454953,"name":"Adam Fillion","orcid":null,"position":5,"is_corresponding":false},{"id":583891,"name":"Tessa Dickson","orcid":null,"position":6,"is_corresponding":false},{"id":700378,"name":"Paul A. MacAry","orcid":"0000-0002-1139-8996","position":7,"is_corresponding":false},{"id":225146,"name":"Patricia A. Darrah","orcid":"0000-0002-0035-2802","position":8,"is_corresponding":false},{"id":225156,"name":"Robert A. Seder","orcid":"0000-0003-3133-0849","position":9,"is_corresponding":false},{"id":656653,"name":"Natalia T. Freund","orcid":"0000-0002-5386-502X","position":10,"is_corresponding":false},{"id":816235,"name":"Babak Javid","orcid":"0000-0002-6354-6305","position":11,"is_corresponding":false},{"id":1061996,"name":"Rania Bouzeyen","orcid":"0000-0002-5784-1025","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T02:55:03.976486Z","pmid":"40747430","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":[]}