{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T12:16:41Z","timestamp":1791461801585,"version":"4.3.4"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022077","name":"Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022077","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The mechanisms underlying innate immune memory (trained immunity) comprise epigenetic reprogramming of transcriptional pathways associated with alterations of intracellular metabolism. While the mechanisms of innate immune memory carried out by immune cells are well characterized, such processes in non-immune cells, are poorly understood. The opportunistic pathogen, <jats:italic>Staphylococcus aureus<\/jats:italic>, is responsible for a multitude of human diseases, including pneumonia, endocarditis and osteomyelitis, as well as animal infections, including chronic cattle mastitis that are extremely difficult to treat. An induction of innate immune memory may be considered as a therapeutic alternative to fight <jats:italic>S. aureus<\/jats:italic> infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In the current work, we demonstrated the development of innate immune memory in non-immune cells during S. aureus infection employing a combination of techniques including Enzyme-linked immunosorbent assay (ELISA), microscopic analysis, and cytometry. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that training of human osteoblast-like MG-63 cells and lung epithelial A549 cells with \u03b2-glucan increased IL-6 and IL-8 production upon a stimulation with <jats:italic>S. aureus<\/jats:italic>, concomitant with histones modifications. IL-6 and IL-8 production was positively correlated with an acetylation of histone 3 at lysine 27 (H3K27), thus suggesting epigenetic reprogramming in these cells. An addition of the ROS scavenger N-Acetylcysteine, NAC, prior to \u03b2-glucan pretreatment followed by an exposure to <jats:italic>S. aureus<\/jats:italic>, resulted in decreased IL-6 and IL-8 production, thereby supporting the involvement of ROS in the induction of innate immune memory. Exposure of cells to <jats:italic>Lactococcus lactis<\/jats:italic> resulted in increased IL-6 and IL-8 production by MG-63 and A549 cells upon a stimulation with S. aureus that was correlated with H3K27 acetylation, suggesting the ability of this beneficial bacterium to induce innate immune memory. <\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This work improves our understanding of innate immune memory in non-immune cells in the context of <jats:italic>S. aureus<\/jats:italic> infection. In addition to known inducers, probiotics may represent good candidates for the induction of innate immune memory. Our findings may help the development of alternative therapeutic approaches for the prevention of <jats:italic>S. aureus<\/jats:italic> infection. <\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1138539","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T05:27:11Z","timestamp":1685510831000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Development of innate immune memory by non-immune cells during Staphylococcus aureus infection depends on reactive oxygen species"],"prefix":"10.3389","volume":"14","author":[{"given":"Emmanuel","family":"Chaumond","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Peron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Le Gouar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9ric","family":"Gu\u00e9don","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Le Loir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gw\u00e9na\u00ebl","family":"Jan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Berkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1098","article-title":"Trained immunity: a program of innate immune memory in health and disease","volume":"352","author":"Netea","year":"2016","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0025-4","article-title":"Therapeutic targeting of trained immunity","volume":"18","author":"Mulder","year":"2019","journal-title":"Nat Rev Drug Discov"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0285-6","article-title":"Defining trained immunity and its role in health and disease","volume":"20","author":"Netea","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2007.09.002","article-title":"Macrophage receptors implicated in the \u201cadaptive\u201d form of innate immunity","volume":"9","author":"Bowdish","year":"2007","journal-title":"Microbes Infect"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2018.03225","article-title":"Trained immunity carried by non-immune cells","volume":"9","author":"Hamada","year":"2019","journal-title":"Front Microbiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.dci.2019.103597","article-title":"Oral administration of debaryomyces hansenii CBS8339-\u03b2-glucan induces trained immunity in newborn goats","volume":"105","author":"Angulo","year":"2020","journal-title":"Dev Comp Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille calmette-guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B8","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":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz692","article-title":"Trained immunity confers broad-spectrum protection against bacterial infections","volume":"222","author":"Ciarlo","year":"2020","journal-title":"J Infect Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00069-15","article-title":"Clinical significance and pathogenesis of staphylococcal small colony variants in persistent infections","volume":"29","author":"Kahl","year":"2016","journal-title":"Clin Microbiol Rev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-019-0597-0","article-title":"Staphylococcus aureus small colony variants impair host immunity by activating host cell glycolysis and inducing necroptosis","volume":"5","author":"Wong Fok Lung","year":"2020","journal-title":"Nat Microbiol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2013.05.015","article-title":"Staphylococcus aureus osteomyelitis: bad to the bone","volume":"13","author":"Olson","year":"2013","journal-title":"Cell Host Microbe"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.2013.827891","article-title":"Pathogenesis of staphylococcus aureus necrotizing pneumonia: the role of PVL and an influenza coinfection","volume":"11","author":"L\u00f6ffler","year":"2013","journal-title":"Expert Rev Anti Infect Ther"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3168\/jds.2019-17433","article-title":"Clinical presentation and immune characteristics in first-lactation Holstein-friesian cows following intramammary infection with genotypically distinct staphylococcus aureus strains","volume":"103","author":"Niedziela","year":"2020","journal-title":"J Dairy Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1808353115","article-title":"Protective immunity in recurrent staphylococcus aureus infection reflects localized immune signatures and macrophage-conferred memory","volume":"115","author":"Chan","year":"2018","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.854242","article-title":"Transcriptome architecture of osteoblastic cells infected with staphylococcus aureus reveals strong inflammatory responses and signatures of metabolic and epigenetic dysregulation","volume":"12","author":"Nicolas","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3A0120-114R","article-title":"TLR8 and complement C5 induce cytokine release and thrombin activation in human whole blood challenged with gram-positive bacteria","volume":"107","author":"Ehrnstr\u00f6m","year":"2020","journal-title":"J Leukoc Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.745332","article-title":"Molecular and cellular mechanisms modulating trained immunity by various cell types in response to pathogen encounter","volume":"12","author":"Acevedo","year":"2021","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7310","article-title":"Epigenetics and trained immunity","volume":"29","author":"van der Heijden","year":"2018","journal-title":"Antioxid. Redox Signal"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1080\/1040841X.2017.1373063","article-title":"Epigenetic regulation in bacterial infections: targeting histone deacetylases","volume":"44","author":"Grabiec","year":"2018","journal-title":"Crit Rev Microbiol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1093\/embo-reports\/kvf053","article-title":"Histone acetylation: a switch between repressive and permissive chromatin: second in review series on chromatin dynamics","volume":"3","author":"Eberharter","year":"2002","journal-title":"EMBO Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"B23","doi-asserted-by":"publisher","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":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2014.66","article-title":"Expert consensus document. the international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic","volume":"11","author":"Hill","year":"2014","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3390\/biom11101402","article-title":"Probiotics and trained immunity","volume":"11","author":"Cortes-Perez","year":"2021","journal-title":"Biomolecules"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.12.1.11","article-title":"Human interferon: mass production in a newly established cell line, MG-63","volume":"12","author":"Billiau","year":"1977","journal-title":"Antimicrob Agents Chemother"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-260513","article-title":"Phenol-soluble modulin \u03b1 induces G2\/M phase transition delay in eukaryotic HeLa cells","volume":"29","author":"Deplanche","year":"2015","journal-title":"FASEB J"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2001.02470.x","article-title":"Pleiotropic transcriptional repressor CodY senses the intracellular pool of branched-chain amino acids in Lactococcus lactis","volume":"40","author":"Gu\u00e9don","year":"2001","journal-title":"Mol Microbiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.529131","article-title":"Novel structural features in candida albicans hyphal glucan provide a basis for differential innate immune recognition of hyphae versus yeast","volume":"289","author":"Lowman","year":"2014","journal-title":"J Biol Chem"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2549-1_24","article-title":"Isolation, physicochemical characterization, labeling, and biological evaluation of mannans and glucans","volume":"2542","author":"Kruppa","year":"2022","journal-title":"Methods Mol Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00349-16","article-title":"In vitro experimental model of trained innate immunity in human primary monocytes","volume":"23","author":"Bekkering","year":"2016","journal-title":"Clin Vaccine Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063279","article-title":"Staphylococcus aureus-induced G2\/M phase transition delay in host epithelial cells increases bacterial infective efficiency","volume":"8","author":"Alekseeva","year":"2013","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","first-page":"8","DOI":"10.4028\/www.scientific.net\/KEM.824.8","article-title":"Promotion of osteoblast proliferation activated by betaglucan (BG) derived from yeast sludge","volume":"824","author":"Rujanant","year":"2019","journal-title":"Key Eng Mater."},{"key":"B34","article-title":"Use of lysostaphin to remove cell-adherent staphylococci during in vitro assays of phagocyte function","volume":"59","author":"Easmon","year":"1978","journal-title":"Br J Exp Pathol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.634774","article-title":"Antiretroviral drugs regulate epigenetic modification of cardiac cells through modulation of H3K9 and H3K27 acetylation","volume":"8","author":"Kashyap","year":"2021","journal-title":"Front Cardiovasc Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1002\/cyto.a.20151","article-title":"New method to detect histone acetylation levels by flow cytometry","author":"Ronzoni","year":"2005","journal-title":"Cytom. Part A"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.13204","article-title":"Involvement of caspase-1 in inflammasomes activation and bacterial clearance in s. aureus-infected osteoblast-like MG-63 cells","volume":"22","author":"Lima Leite","year":"2020","journal-title":"Cell Microbiol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/43710","article-title":"Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors","volume":"401","author":"Finnin","year":"1999","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27010075","article-title":"Effects of NAC and Gallic acid on the proliferation inhibition and induced death of lung cancer cells with different antioxidant capacities","volume":"27","author":"Liao","year":"2021","journal-title":"Molecules"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041390227","article-title":"Analysis of the growth factor requirements for stimulation of WI-38 cells after extended periods of density-dependent growth arrest","volume":"139","author":"Owen","year":"1989","journal-title":"J Cell Physiol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04265-w","article-title":"Emergence of methicillin resistance predates the clinical use of antibiotics","volume":"602","author":"Larsen","year":"2022","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00084-17","article-title":"Staphylococcal osteomyelitis: disease progression, treatment challenges, and future directions","volume":"31","author":"Kavanagh","year":"2018","journal-title":"Clin Microbiol Rev"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201000115","article-title":"Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection","volume":"3","author":"Tuchscherr","year":"2011","journal-title":"EMBO Mol Med"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.09.029","article-title":"Cellular mechanisms and regulation of quiescence","volume":"55","author":"Marescal","year":"2020","journal-title":"Dev Cell"},{"key":"B45","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s11274-021-03182-4","article-title":"Biochanin a as an \u03b1-hemolysin inhibitor for combating methicillin-resistant staphylococcus aureus infection","volume":"38","author":"Feng","year":"2021","journal-title":"World J Microbiol Biotechnol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/molecules26133865","article-title":"Rubesanolides f and G: two novel lactone-type norditerpenoids from isodon rubescens","volume":"26","author":"He","year":"2021","journal-title":"Molecules"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26227","article-title":"Differentially regulated gene expression in quiescence versus senescence and identification of ARID5A as a quiescence associated marker","volume":"233","author":"Anwar","year":"2018","journal-title":"J Cell Physiol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1146\/annurev.biochem.70.1.81","article-title":"Histone acetyltransferases","volume":"70","author":"Roth","year":"2001","journal-title":"Annu Rev Biochem"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-016-0855-8","article-title":"TLR9 mediates S. aureus killing inside osteoblasts via induction of oxidative stress","volume":"16","author":"Mohamed","year":"2016","journal-title":"BMC Microbiol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"7694","DOI":"10.1038\/s41598-019-44213-3","article-title":"Staphylococcus aureus induces DNA damage in host cell","volume":"9","author":"Deplanche","year":"2019","journal-title":"Sci Rep"},{"key":"B51","doi-asserted-by":"publisher","first-page":"52","DOI":"10.14336\/AD.2014.050052","article-title":"New nucleophilic mechanisms of ros-dependent epigenetic modifications: comparison of aging and cancer","volume":"5","author":"Afanas\u2019ev","year":"2013","journal-title":"Aging Dis"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108368","article-title":"Intramacrophage ROS primes the innate immune system via JAK\/STAT and toll activation","volume":"33","author":"Chakrabarti","year":"2020","journal-title":"Cell Rep"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3920\/BM2015.0094","article-title":"Interaction of mouse splenocytes and macrophages with bacterial strains in vitro: the effect of age in the immune response","volume":"7","author":"Van Beek","year":"2016","journal-title":"Benef Microbes"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.759649","article-title":"Emulsion-based postbiotic formulation is comparable to viable cells in eliciting a localized immune response in dairy cows with chronic mastitis","volume":"13","author":"Mathur","year":"2022","journal-title":"Front Microbiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1138539\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T05:27:15Z","timestamp":1685510835000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1138539\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,31]]},"references-count":54,"alternative-id":["10.3389\/fimmu.2023.1138539"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1138539","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,31]]},"article-number":"1138539"}}