{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T19:18:30Z","timestamp":1793992710185,"version":"4.8.0"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The nonspecific protection provided by the innate immune system can be enhanced through training with stimuli, a phenomenon called \u2018trained immunity\u2019. However, it remains unknown if distinct training programs with various functional outcomes can be induced. Here, we show that two training agents, flunisolide and myricetin, distinctively train and modulate the immune response against\n                    <jats:italic>in vivo Listeria monocytogenes<\/jats:italic>\n                    infection. Training with either agent led to significant reduction in pathogen burden but differed in the resulting immune functions. Training with myricetin led to the expansion of myeloid progenitor lineages, rapid cell recruitment, and enhanced phagocytosis. In contrast, training with flunisolide led to expansion of stem cell and multipotent progenitor populations, increase in antigen processing, and faster T cell expansion. We provide preliminary evidence that this divergent training outcomes may arise from agent-specific modulation of transcription factors. This study importantly shows that training can be directed at both the innate response and the onset of the adaptive response, highlighting the potential of modulating distinct training programs to influence protective immune responses.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1868138","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:36:46Z","timestamp":1784871406000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Agent-specific training directs distinctive immune response against Listeria monocytogenes infection"],"prefix":"10.3389","volume":"17","author":[{"given":"Marie","family":"Kim","sequence":"first","affiliation":[{"name":"Pritzker School of Molecular Engineering, University of Chicago","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey G.","family":"Main","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Chicago","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron P.","family":"Esser-Kahn","sequence":"additional","affiliation":[{"name":"Pritzker School of Molecular Engineering, University of Chicago","place":["Chicago, IL, United States"]},{"name":"CZI Biohub Investigator","place":["Chicago, IL, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir240","article-title":"Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period","volume":"204","author":"Aaby","year":"2011","journal-title":"J Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.051","article-title":"Activate: Randomized clinical trial of BCG vaccination against infection in the elderly","volume":"183","author":"Giamarellos-Bourboulis","year":"2020","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08659-3","article-title":"Outcomes of controlled human malaria infection after BCG vaccination","volume":"10","author":"Walk","year":"2019","journal-title":"Nat Commun"},{"key":"B4","doi-asserted-by":"publisher","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":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004485","article-title":"Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer","volume":"10","author":"Buffen","year":"2014","journal-title":"PloS Pathog"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008404","article-title":"New live attenuated tuberculosis vaccine MTBVAC induces trained immunity and confers protection against experimental lethal pneumonia","volume":"16","author":"Taranc\u00f3n","year":"2020","journal-title":"PloS Pathog"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.111284","article-title":"Staphylococcus aureus induced trained immunity in macrophages confers heterologous protection against gram-negative bacterial infection","volume":"27","author":"Carlile","year":"2024","journal-title":"iScience"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.723393","article-title":"Trained immunity confers prolonged protection from listeriosis","volume":"12","author":"Th\u00e9roude","year":"2021","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/iai.20.3.804-810.1978","article-title":"Protective effect of glucan against systemic Staphylococcus aureus septicemia in normal and leukemic mice","volume":"20","author":"Di Luzio","year":"1978","journal-title":"Infect Immun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107634","article-title":"\u03b2-Glucan induces protective trained immunity against Mycobacterium tuberculosis infection: A key role for IL-1","volume":"31","author":"Moorlag","year":"2020","journal-title":"Cell Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"6204","DOI":"10.1126\/science.1251086","article-title":"Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity","volume":"345","author":"Saeed","year":"2014","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.cell.2016.09.034","article-title":"\u03b2-Glucan reverses the epigenetic state of LPS-induced immunological tolerance","volume":"167","author":"Novakovic","year":"2016","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02103-4","article-title":"Systemic administration of \u03b2-glucan induces immune training in microglia","volume":"18","author":"Heng","year":"2021","journal-title":"J Neuroinflamm"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2012.06.006","article-title":"Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes","volume":"12","author":"Quintin","year":"2012","journal-title":"Cell Host Microbe"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/jimmun\/vkaf283.2696","article-title":"Innate immune memory induced by MDP, B-glucan or SYK inhibition accelerates trained immunity-based elimination of HIV infected cells from PBMCs of PLWH 9273","volume":"214","author":"Kaur","year":"2025","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1161\/CIRCRESAHA.119.315800","article-title":"Catecholamines induce trained immunity in monocytes in vitro and in vivo","volume":"127","author":"van der Heijden","year":"2020","journal-title":"Circ Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110028","article-title":"Single-cell transcriptomic profiles reveal changes associated with BCG-induced trained immunity and protective effects in circulating monocytes","volume":"37","author":"Kong","year":"2021","journal-title":"Cell Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.12.005","article-title":"Multi-omics analysis of innate and adaptive responses to BCG vaccination reveals epigenetic cell states that predict trained immunity","volume":"57","author":"Moorlag","year":"2024","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille Calmette-Gu\u00e9rin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc Natl Acad Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.109030","article-title":"Recognition of yeast \u03b2-glucan particles triggers immunometabolic signaling required for trained immunity","volume":"27","author":"Horneck Johnston","year":"2024","journal-title":"iScience"},{"key":"B21","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41590-019-0402-5","article-title":"Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation","volume":"20","author":"Chavakis","year":"2019","journal-title":"Nat Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cell.2017.12.013","article-title":"Western diet triggers NLRP3-dependent innate immune reprogramming","volume":"172","author":"Christ","year":"2018","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2045","article-title":"Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity","volume":"12","author":"Chang","year":"2011","journal-title":"Nat Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"7677","DOI":"10.1038\/nature24271","article-title":"Inflammatory memory sensitizes skin epithelial stem cells to tissue damage","volume":"550","author":"Naik","year":"2017","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/prd.12421","article-title":"Maladaptive trained immunity and clonal hematopoiesis as potential mechanistic links between periodontitis and inflammatory comorbidities","volume":"89","author":"Hajishengallis","year":"2022","journal-title":"Periodontol 2000"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.303887","article-title":"Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes","volume":"34","author":"Bekkering","year":"2014","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/s41590-023-01700-0","article-title":"BCG vaccination stimulates integrated organ immunity by feedback of the adaptive immune response to imprint prolonged innate antiviral resistance","volume":"25","author":"Lee","year":"2024","journal-title":"Nat Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.aea1260","article-title":"Mucosal vaccination in mice provides protection from diverse respiratory threats","volume":"392","author":"Zhang","year":"2026","journal-title":"Science"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.08.018","article-title":"Stimulus-specific responses in innate immunity: Multilayered regulatory circuits","volume":"54","author":"Luecke","year":"2021","journal-title":"Immunity"},{"key":"B30","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.cels.2022.12.012","article-title":"Quantifying stimulus-response specificity to probe the functional state of macrophages","volume":"14","author":"Sheu","year":"2023","journal-title":"Cell Syst"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00688-13","article-title":"Trained immunity or tolerance: Opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors","volume":"21","author":"Ifrim","year":"2014","journal-title":"Clin Vaccine Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1073\/pnas.2400413121","article-title":"High-throughput screen identifies non inflammatory small molecule inducers of trained immunity","volume":"121","author":"Knight","year":"2024","journal-title":"Proc Natl Acad Sci USA"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1101\/2025.01.22.634275","article-title":"Innate immune memory is stimulus specific","author":"O\u2019Farrell","year":"2025","journal-title":"bioRxiv"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00680","article-title":"GM-CSF and IL-3 modulate human monocyte TNF-\u03b1 production and renewal in in vitro models of trained immunity","volume":"7","author":"Borriello","year":"2017","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.9.4805-4811.2002","article-title":"Comparison of host resistance to primary and secondary Listeria monocytogenes infections in mice by intranasal and intravenous routes","volume":"70","author":"Mizuki","year":"2002","journal-title":"Infect Immun"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cell.2017.11.034","article-title":"Modulation of myelopoiesis progenitors is an integral component of trained immunity","volume":"172","author":"Mitroulis","year":"2018","journal-title":"Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cell.2017.12.031","article-title":"BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis","volume":"172","author":"Kaufmann","year":"2018","journal-title":"Cell"},{"key":"B38","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.chom.2020.05.014","article-title":"BCG vaccination in humans elicits trained immunity via the hematopoietic progenitor compartment","volume":"28","author":"Cirovic","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110184","article-title":"Trained immunity induction by the inactivated mucosal vaccine MV130 protects against experimental viral respiratory infections","volume":"38","author":"Brandi","year":"2022","journal-title":"Cell Rep"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41435-025-00357-z","article-title":"The epigenomic landscape of bronchial epithelial cells reveals the establishment of trained immunity","volume":"26","author":"Bigot","year":"2025","journal-title":"Genes Immun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1138539","article-title":"Development of innate immune memory by non-immune cells during Staphylococcus aureus infection depends on reactive oxygen species","volume":"14","author":"Chaumond","year":"2023","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111760","article-title":"Proinflammatory cytokine signaling required for the generation of natural killer cell memory","volume":"209","author":"Sun","year":"2012","journal-title":"J Exp Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2113329119","article-title":"Developmentally distinct CD4+ Treg lineages shape the CD8+ T cell response to acute Listeria infection","volume":"119","author":"Dolina","year":"2022","journal-title":"Proc Natl Acad Sci"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112487","article-title":"A single-cell view on host immune transcriptional response to in vivo BCG-induced trained immunity","volume":"42","author":"Li","year":"2023","journal-title":"Cell Rep"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/BF01966302","article-title":"Binding affinities of rimexolone (ORG 6216), flunisolide and their putative metabolites for the glucocorticoid receptor of human synovial tissue","volume":"30","author":"Hochhaus","year":"1990","journal-title":"Agents Actions"},{"key":"B46","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.rdc.2015.08.002","article-title":"Corticosteroids: Mechanisms of action in health and disease","volume":"42","author":"Ramamoorthy","year":"2016","journal-title":"Rheum Dis Clin N Am"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1038\/s41467-018-03780-1","article-title":"Cryptic glucocorticoid receptor-binding sites pervade genomic NF-\u03baB response elements","volume":"9","author":"Hudson","year":"2018","journal-title":"Nat Commun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.8.3919","article-title":"Glucocorticoids repress NF-\u03baB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell","volume":"97","author":"De Bosscher","year":"2000","journal-title":"Proc Natl Acad Sci"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5234.283","article-title":"Role of transcriptional activation of I\u03baB\u03b1 in mediation of immunosuppression by glucocorticoids","volume":"270","author":"Scheinman","year":"1995","journal-title":"Science"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.11.3365","article-title":"Glucocorticoid receptor activation of the I\u03baB\u03b1 promoter within chromatin","volume":"12","author":"Deroo","year":"2001","journal-title":"Mol Biol Cell"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114460","article-title":"Identification of MAP kinase kinase 3 as a protein target of myricetin in non-small cell lung cancer cells","volume":"161","author":"Gu","year":"2023","journal-title":"BioMed Pharmacother"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.10.027","article-title":"MKK4 is a novel target for the inhibition of tumor necrosis factor-\u03b1-induced vascular endothelial growth factor expression by myricetin","volume":"77","author":"Kim","year":"2009","journal-title":"Biochem Pharmacol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1002\/jsfa.5733","article-title":"Myricetin attenuates lipopolysaccharide\u2010stimulated activation of mouse bone marrow\u2010derived dendritic cells through suppression of IKK\/NF\u2010\u03baB and MAPK signalling pathways","volume":"93","author":"Fu","year":"2013","journal-title":"J Sci Food Agric"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/ijms11114348","article-title":"Myricetin protects cells against oxidative stress-induced apoptosis via regulation of PI3K\/Akt and MAPK signaling pathways","volume":"11","author":"Kang","year":"2010","journal-title":"Int J Mol Sci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2025.116202","article-title":"In vitro protocol demonstrating five functional steps of trained immunity in mice: Implications on biomarker discovery and translational research","volume":"44","author":"Gonz\u00e1lez-P\u00e9rez","year":"2025","journal-title":"Cell Rep"},{"key":"B56","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/s44320-024-00047-4","article-title":"Dynamical and combinatorial coding by MAPK p38 and NF\u03baB in the inflammatory response of macrophages","volume":"20","author":"Luecke","year":"2024","journal-title":"Mol Syst Biol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1101\/gr.118042.110","article-title":"Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes","volume":"21","author":"Rao","year":"2011","journal-title":"Genome Res"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2016.05.009","article-title":"MEK2 controls the activation of MKK3\/MKK6-p38 axis involved in the MDA-MB-231 breast cancer cell survival: Correlation with cyclin D1 expression","volume":"28","author":"Huth","year":"2016","journal-title":"Cell Signal"},{"key":"B59","doi-asserted-by":"publisher","first-page":"5670","DOI":"10.1038\/s41467-019-13636-x","article-title":"Trained immunity modulates inflammation-induced fibrosis","volume":"10","author":"Jeljeli","year":"2019","journal-title":"Nat Commun"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1159\/000355628","article-title":"Long-lasting effects of BCG vaccination on both heterologous Th1\/Th17 responses and innate trained immunity","volume":"6","author":"Kleinnijenhuis","year":"2014","journal-title":"J Innate Immun"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.09.042","article-title":"Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity","volume":"175","author":"Yao","year":"2018","journal-title":"Cell"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/nri2171","article-title":"Evolving functions of endothelial cells in inflammation","volume":"7","author":"Pober","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.040","article-title":"The stromal intervention: Regulation of immunity and inflammation at the epithelial-mesenchymal barrier","volume":"168","author":"Nowarski","year":"2017","journal-title":"Cell"},{"key":"B64","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/s41586-020-2424-4","article-title":"Structural cells are key regulators of organ-specific immune responses","volume":"583","author":"Krausgruber","year":"2020","journal-title":"Nature"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1126\/science.add5327","article-title":"Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis","volume":"380","author":"Burdziak","year":"2023","journal-title":"Science"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3336","article-title":"The epigenetics of epithelial-mesenchymal plasticity in cancer","volume":"19","author":"Tam","year":"2013","journal-title":"Nat Med"},{"key":"B67","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/s41420-024-02275-x","article-title":"The plasticity of epithelial cells and its potential in the induced differentiation of gastric cancer","volume":"10","author":"Yan","year":"2024","journal-title":"Cell Death Discov"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1868138\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T05:36:46Z","timestamp":1784871406000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1868138\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":67,"alternative-id":["10.3389\/fimmu.2026.1868138"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1868138","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]},"article-number":"1868138"}}