{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T20:05:53Z","timestamp":1785528353462,"version":"3.56.0"},"reference-count":51,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council of Science and Technology (CONACyT)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bacillus Calmette\u2013Gu\u00e9rin (BCG) vaccine is an attenuated strain of Mycobacterium bovis that provides weak protection against tuberculosis (TB). Mast cells (MCs) are tissue-resident immune cells strategically that serve as the first line of defence against pathogenic threats. In this study, we investigated the response of human MCs (hMCs) to BCG. We found that na\u00efve hMCs exposed to BCG did not secrete cytokines, degranulate, or support the uptake and intracellular growth of bacteria. Since we could show that in hMCs IL-33 promotes the transcription of host-pathogen interaction, cell adhesion and activation genes, we used IL-33 for cell priming. The treatment of hMCs with IL-33, but not IFN-\u03b3, before BCG stimulation increased IL-8, MCP-1 and IL-13 secretion, and induced an enhanced expression of the mycobacteria-binding receptor CD48. These effects were comparable to those caused by the recombinant Mycobacterium tuberculosis (Mtb) 19-KDa lipoprotein. Finally, stimulation of hMCs with IL-33 incremented MC-BCG interactions. Thus, we propose that IL-33 may improve the immunogenicity of BCG vaccine by sensitising hMCs.<\/jats:p>","DOI":"10.3390\/ijms23147549","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T22:11:47Z","timestamp":1657231907000},"page":"7549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Bacillus Calmette\u2013Gu\u00e9rin-Induced Human Mast Cell Activation Relies on IL-33 Priming"],"prefix":"10.3390","volume":"23","author":[{"given":"Karen M.","family":"Garcia-Rodriguez","sequence":"first","affiliation":[{"name":"Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK"},{"name":"School of Materials, Faculty of Science and Engineering, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8152-2155","authenticated-orcid":false,"given":"Anu","family":"Goenka","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4800-7717","authenticated-orcid":false,"given":"Darren D.","family":"Thomson","sequence":"additional","affiliation":[{"name":"Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK"},{"name":"MRC Centre for Medical Mycology, University of Exeter, Exeter EX4 4PY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajia","family":"Bahri","sequence":"additional","affiliation":[{"name":"Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Tontini","sequence":"additional","affiliation":[{"name":"Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Salcman","sequence":"additional","affiliation":[{"name":"Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rogelio","family":"Hernandez-Pando","sequence":"additional","affiliation":[{"name":"Experimental Pathology Section, Department of Pathology, National Institute of Medical Sciences and Nutrition \u201cSalvador Zubir\u00e1n\u201d, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5764-8516","authenticated-orcid":false,"given":"Silvia","family":"Bulfone-Paus","sequence":"additional","affiliation":[{"name":"Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.3389\/fimmu.2017.01134","article-title":"What Have We Learnt about BCG Vaccination in the Last 20\u2009Years?","volume":"8","author":"Dockrell","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1586\/14760584.2016.1170599","article-title":"Why don\u2019t we have an effective tuberculosis vaccine yet?","volume":"15","author":"Davenne","year":"2016","journal-title":"Expert Rev. Vaccines"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1080\/21645515.2019.1706930","article-title":"BCG: A vaccine with multiple faces","volume":"16","author":"Unzueta","year":"2020","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1080\/14760584.2017.1333906","article-title":"BCG and protection against inflammatory and auto-immune diseases","volume":"16","author":"Locht","year":"2017","journal-title":"Expert Rev. Vaccines"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6248","DOI":"10.3892\/mmr.2017.7383","article-title":"Anti-allergic action of bacillus Calmette-Guerin extract in experimental mast cell-mediated anaphylactic models","volume":"16","author":"Sun","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.3389\/fonc.2019.01270","article-title":"Immune Responses in Bladder Cancer-Role of Immune Cell Populations, Prognostic Factors and Therapeutic Implications","volume":"9","author":"Oseph","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e7404","DOI":"10.7717\/peerj.7404","article-title":"Therapeutic effect of Bacillus Calmette-Guerin polysaccharide nucleic acid on mast cell at the transcriptional level","volume":"7","author":"Yan","year":"2019","journal-title":"PeerJ"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1111\/joim.13037","article-title":"Clinical and molecular insights into BCG immunotherapy for melanoma","volume":"288","author":"Kremenovic","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.chom.2017.12.010","article-title":"BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity","volume":"23","author":"Arts","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41577-020-0337-y","article-title":"BCG-induced trained immunity: Can it offer protection against COVID-19?","volume":"20","author":"Netea","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"43682","DOI":"10.1038\/srep43682","article-title":"Scrutiny of Mycobacterium tuberculosis 19 kDa antigen proteoforms provides new insights in the lipoglycoprotein biogenesis paradigm","volume":"7","author":"Parra","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/j.1365-3083.2005.01569.x","article-title":"Increased Expression of Mycobacterium tuberculosis 19 kDa Lipoprotein Obliterates the Protective Efficacy of BCG by Polarizing Host Immune Responses to the Th2 Subtype","volume":"61","author":"Rao","year":"2005","journal-title":"Scand. J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14411","DOI":"10.1038\/s41598-018-32799-z","article-title":"Comparison of immunogenicity and vaccine efficacy between heat-shock proteins, HSP70 and GrpE, in the DnaK operon of Mycobacterium tuberculosis","volume":"8","author":"Kim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3389\/fimmu.2017.00407","article-title":"Immune Responses to Bacillus Calmette-Gu\u00e9rin Vaccination: Why Do They Fail to Protect against Mycobacterium tuberculosis?","volume":"8","author":"Moliva","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1111\/imr.12623","article-title":"The contribution of mast cells to bacterial and fungal infection immunity","volume":"282","author":"Piliponsky","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.3389\/fimmu.2017.01290","article-title":"The Role of Mast Cells in Tuberculosis: Orchestrating Innate Immune Crosstalk?","volume":"8","author":"Goenka","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.coph.2018.05.004","article-title":"Mast cell activators as novel immune regulators","volume":"41","author":"Choi","year":"2018","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"364","DOI":"10.3389\/fimmu.2019.00364","article-title":"IL33: Roles in Allergic Inflammation and Therapeutic Perspectives","volume":"10","author":"Chan","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.jaci.2016.09.049","article-title":"IL-33 fine tunes mast cell degranulation and chemokine production at the single-cell level","volume":"140","author":"Joulia","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"104380","DOI":"10.1016\/j.cellimm.2021.104380","article-title":"Mast cells modulate early responses to Mycobacterium bovis Bacillus Calmette-Guerin by phagocytosis and formation of extracellular traps","volume":"365","author":"Naqvi","year":"2021","journal-title":"Cell. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5590","DOI":"10.4049\/jimmunol.170.11.5590","article-title":"Mast Cell Activation by Mycobacterium tuberculosis: Mediator Release and Role of CD48","volume":"170","author":"Abraham","year":"2003","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Dowell, A.C., Cobby, E., Wen, K., Devall, A.J., During, V., Anderson, J., James, N.D., Cheng, K.K., Zeegers, M.P., and Bryan, R.T. (2017). Interleukin-17-positive mast cells influence outcomes from BCG for patients with CIS: Data from a comprehensive characterisation of the immune microenvironment of urothelial bladder cancer. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0184841"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/nrurol.2017.166","article-title":"Mastering the immune microenvironment","volume":"14","author":"Stone","year":"2017","journal-title":"Nat. Rev. Urol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ajpath.2015.06.024","article-title":"The Role of Mast Cells in Bacterial Infection","volume":"186","author":"Johnzon","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/j.1365-2567.2007.02564.x","article-title":"Mycobacterium tuberculosis heat-shock protein 70 impairs maturation of dendritic cells from bone marrow precursors, induces interleukin-10 production and inhibits T-cell proliferation in vitro","volume":"121","author":"Motta","year":"2007","journal-title":"Immunology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/labinvest.3700663","article-title":"IL-33 can promote survival, adhesion and cytokine production in human mast cells","volume":"87","author":"Iikura","year":"2007","journal-title":"Lab. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1111\/imm.12524","article-title":"Interferon-\u03b3 enhances both the anti-bacterial and the pro-inflammatory response of human mast cells to Staphylococcus aureus","volume":"146","author":"Swindle","year":"2015","journal-title":"Immunology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1038\/nri2782","article-title":"Mast cell-orchestrated immunity to pathogens","volume":"10","author":"Abraham","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/iid3.295","article-title":"Human mast cells exhibit an individualized pattern of antimicrobial responses","volume":"8","author":"Bahri","year":"2020","journal-title":"Immunity Inflamm. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1128\/IAI.01004-09","article-title":"Infection of Mast Cells with Live Streptococci Causes a Toll-Like Receptor 2- and Cell-Cell Contact-Dependent Cytokine and Chemokine Response","volume":"78","author":"Ronnberg","year":"2010","journal-title":"Infect. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6831","DOI":"10.1128\/IAI.73.10.6831-6837.2005","article-title":"Effect of Deletion or Overexpression of the 19-Kilodalton Lipoprotein Rv3763 on the Innate Response to Mycobacterium tuberculosis","volume":"73","author":"Stewart","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"20961","DOI":"10.1074\/jbc.M411379200","article-title":"Mycobacterium Tuberculosis Heat Shock Proteins Use Diverse Toll-like Receptor Pathways to Activate Pro-inflammatory Signals","volume":"280","author":"Bulut","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.3892\/mmr.2014.3070","article-title":"Mycobacterium tuberculosis 19-kDa lipoprotein induces Toll-like receptor 2-dependent peroxisome proliferator-activated receptor \u03b3 expression and promotes inflammatory responses in human macrophages","volume":"11","author":"Liu","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3800","DOI":"10.1002\/1873-3468.12273","article-title":"Mycobacterium tuberculosis lipoproteins in virulence and immunity-fighting with a double-edged sword","volume":"590","author":"Becker","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6603","DOI":"10.1128\/IAI.72.11.6603-6614.2004","article-title":"Prolonged Toll-Like Receptor Signaling by Mycobacterium tuberculosis and Its 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Induced Regulation of Selected Genes in Macrophages","volume":"72","author":"Pai","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4323","DOI":"10.4049\/jimmunol.176.7.4323","article-title":"Mycobacterium tuberculosis 19-kDa Lipoprotein Inhibits IFN-\u03b3-Induced Chromatin Remodeling of MHC2TA by TLR2 and MAPK Signaling","volume":"176","author":"Pennini","year":"2006","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nri2018","article-title":"Role of mast cells in allergic and non-allergic immune responses: Comparison of human and murine data","volume":"7","author":"Bischoff","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/nm1757","article-title":"Mast cell activators: A new class of highly effective vaccine adjuvants","volume":"14","author":"McLachlan","year":"2008","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12703","DOI":"10.1128\/JVI.01182-10","article-title":"Interleukin-1 Family Cytokines as Mucosal Vaccine Adjuvants for Induction of Protective Immunity against Influenza Virus","volume":"84","author":"Kayamuro","year":"2010","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1080\/21645515.2015.1026499","article-title":"Alarmin IL-33 elicits potent TB-specific cell-mediated responses","volume":"11","author":"Villarreal","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1182\/blood-2012-05-434209","article-title":"Intraperitoneal influx of neutrophils in response to IL-33 is mast cell\u2013dependent","volume":"121","author":"Enoksson","year":"2013","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/path.4399","article-title":"The IL-13\/IL-4R\u03b1 axis is involved in tuberculosis-associated pathology","volume":"234","author":"Heitmann","year":"2014","journal-title":"J. Pathol."},{"key":"ref_43","first-page":"1","article-title":"Differential mast cell numbers and characteristics in human tuberculosis pulmonary lesions","volume":"11","author":"Bini","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.4049\/jimmunol.156.4.1490","article-title":"Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells","volume":"156","author":"Malaviya","year":"1996","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1471-4906(01)02156-1","article-title":"The role of mast cells in host defense and their subversion by bacterial pathogens","volume":"23","author":"Varadaradjalou","year":"2002","journal-title":"Trends Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.imbio.2015.09.004","article-title":"Mast cells phagocyte Candida albicans and produce nitric oxide by mechanisms involving TLR2 and Dectin-1","volume":"221","author":"Pinke","year":"2016","journal-title":"Immunobiology"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Espinosa-Cueto, P., Magallanes-Puebla, A., and Mancilla, R. (2020). Phosphate starvation enhances phagocytosis of Mycobacterium bovis\/BCG by macrophages. BMC Immunol., 21.","DOI":"10.1186\/s12865-020-00364-x"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/iid3.59","article-title":"IL-33 promotes MHC class II expression in murine mast cells","volume":"3","author":"Ito","year":"2015","journal-title":"Immunity Inflamm. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"D766","DOI":"10.1093\/nar\/gky955","article-title":"GENCODE reference annotation for the human and mouse genomes","volume":"47","author":"Frankish","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7549\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:44:08Z","timestamp":1760139848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,7]]},"references-count":51,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147549"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147549","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,7]]}}}