{"doi":"10.1101/2023.07.16.549208","title":"Protective intravenous BCG vaccination induces enhanced immune signaling in the airways","abstract":"Abstract Intradermal (ID) Bacillus Calmette–Guérin (BCG) is the most widely administered vaccine in the world. However, ID-BCG fails to achieve the level of protection needed in adults to alter the course of the tuberculosis epidemic. Recent studies in non-human primates have demonstrated high levels of protection against Mycobacterium tuberculosis ( Mtb ) following intravenous (IV) administration of BCG. However, the protective immune features that emerge following IV BCG vaccination remain incompletely defined. Here we used single-cell RNA-sequencing (scRNAseq) to transcriptionally profile 157,114 unstimulated and purified protein derivative (PPD)-stimulated bronchoalveolar lavage (BAL) cells from 29 rhesus macaques immunized with BCG across routes of administration and doses to uncover cell composition-, gene expression-, and biological network-level signatures associated with IV BCG-mediated protection. Our analyses revealed that high-dose IV BCG drove an influx of polyfunctional T cells and macrophages into the airways. These macrophages exhibited a basal activation phenotype even in the absence of PPD-stimulation, defined in part by IFN and TNF-α signaling up to 6 months following BCG immunization. Furthermore, intercellular immune signaling pathways between key myeloid and T cell subsets were enhanced following PPD-stimulation in high-dose IV BCG-vaccinated macaques. High-dose IV BCG also engendered quantitatively and qualitatively stronger transcriptional responses to PPD-stimulation, with a robust Th1-Th17 transcriptional phenotype in T cells, and augmented transcriptional signatures of reactive oxygen species production, hypoxia, and IFN-γ response within alveolar macrophages. Collectively, this work supports that IV BCG immunization creates a unique cellular ecosystem in the airways, which primes and enables local myeloid cells to effectively clear Mtb upon challenge.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":389749,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"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":260804,"name":"Edward B. Irvine","orcid":"0000-0002-8185-6454","position":1,"is_corresponding":false},{"id":91617,"name":"Jacob M. Rosenberg","orcid":"0000-0003-4951-7441","position":2,"is_corresponding":false},{"id":19166,"name":"Marc H. Wadsworth","orcid":"0000-0001-9479-8516","position":3,"is_corresponding":false},{"id":19167,"name":"Travis K. Hughes","orcid":null,"position":4,"is_corresponding":false},{"id":703782,"name":"Matt Sutton","orcid":"0000-0002-6635-2127","position":5,"is_corresponding":false},{"id":56344,"name":"Sarah K. Nyquist","orcid":"0000-0002-9045-3665","position":6,"is_corresponding":false},{"id":945249,"name":"Joshua D. Bromley","orcid":"0000-0001-8692-2740","position":7,"is_corresponding":false},{"id":1160345,"name":"Rajib Mondal","orcid":"0000-0002-9531-9852","position":8,"is_corresponding":false},{"id":18050,"name":"Mario Roederer","orcid":"0000-0001-7448-7040","position":9,"is_corresponding":false},{"id":225156,"name":"Robert A. Seder","orcid":"0000-0003-3133-0849","position":10,"is_corresponding":false},{"id":225146,"name":"Patricia A. Darrah","orcid":"0000-0002-0035-2802","position":11,"is_corresponding":false},{"id":106757,"name":"Galit Alter","orcid":"0000-0002-7680-9215","position":12,"is_corresponding":false},{"id":225155,"name":"JoAnne L. Flynn","orcid":"0000-0001-7874-8981","position":13,"is_corresponding":false},{"id":1413,"name":"Alex K. Shalek","orcid":"0000-0001-5670-8778","position":14,"is_corresponding":false},{"id":91624,"name":"Sarah M. Fortune","orcid":"0000-0001-7565-9975","position":15,"is_corresponding":false},{"id":91622,"name":"Bryan D. Bryson","orcid":"0000-0003-1716-6712","position":16,"is_corresponding":false},{"id":91618,"name":"Joshua M. Peters","orcid":"0000-0001-9163-6706","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T01:18:27.054415Z","pmid":"37502895","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":[]}