{"doi":"10.1101/2024.11.16.623943","title":"IL-33 protects from recurrent <i>C. difficile</i> infection by restoration of humoral immunity","abstract":"ABSTRACT Clostridioides difficile infection (CDI) recurs in one of five patients. Monoclonal antibodies targeting the virulence factor TcdB reduce disease recurrence, suggesting that an inadequate anti-TcdB response to CDI leads to recurrence. In patients with CDI, we discovered that IL-33 measured at diagnosis predicts future recurrence, leading us to test the role of IL-33 signaling in the induction of humoral immunity during CDI. Using a mouse recurrence model, IL-33 was demonstrated to be integral for anti-TcdB antibody production. IL-33 acted via ST2+ ILC2 cells, facilitating germinal center T follicular helper (GC-Tfh) cell generation of antibodies. IL-33 protection from reinfection was antibody-dependent, as μMT KO mice and mice treated with anti-CD20 mAb were not protected. These findings demonstrate the critical role of IL-33 in generating humoral immunity to prevent recurrent CDI. Abstract Figure Graphical Abstract: IL-33 restoration induces toxin-B-specific antibody production via the ILC2-TFH axis. In the left panel, IL-33 remediation increases ILC2s, subsequently inducing TFH directly or indirectly. TFH cell induction is pivotal for the production of antibodies. IL-33 also downregulates type 1 and type 3 immunity, favoring type 2 immunity to enhance host survival and reduce morbidity. The middle panel illustrates antibiotic-induced dysbiosis, resulting in decreased IL-33 levels and reduced antibody production. The right panel demonstrates the protective effect in reinfection, attributed to toxin-specific antibodie generated by IL-33 remediation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":506299,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1357544,"name":"Nicholas Hagspiel","orcid":null,"position":1,"is_corresponding":false},{"id":59348,"name":"Mary K. Young","orcid":"0000-0002-4754-1440","position":2,"is_corresponding":false},{"id":492389,"name":"Md. Jashim Uddin","orcid":"0000-0002-2466-7198","position":3,"is_corresponding":false},{"id":498171,"name":"David Tyus","orcid":"0000-0002-7100-3140","position":4,"is_corresponding":false},{"id":1111844,"name":"Rachel Boone","orcid":"0000-0001-9355-4202","position":5,"is_corresponding":false},{"id":1147729,"name":"Audrey C. Brown","orcid":"0000-0001-5572-0396","position":6,"is_corresponding":false},{"id":323062,"name":"Girija Ramakrishnan","orcid":"0000-0002-9543-3583","position":7,"is_corresponding":false},{"id":613361,"name":"Isaura Rigo","orcid":null,"position":8,"is_corresponding":false},{"id":447023,"name":"Gregory R. Madden","orcid":"0000-0002-5951-3156","position":9,"is_corresponding":false},{"id":59357,"name":"William A. Petri Jr.","orcid":"0000-0002-7268-1218","position":10,"is_corresponding":false},{"id":1239539,"name":"Farha Naz","orcid":"0000-0003-0647-4613","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:10:50.984927Z","pmid":"39605647","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":[]}