{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:07:07Z","timestamp":1790960827669,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T00:00:00Z","timestamp":1700438400000},"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><jats:italic>Helicobacter pylori<\/jats:italic> is a widespread Gram-negative pathogen involved in a variety of gastrointestinal diseases, including gastritis, ulceration, mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. Immune responses aimed at eradication of <jats:italic>H. pylori<\/jats:italic> often prove futile, and paradoxically play a crucial role in the degeneration of epithelial integrity and disease progression. We have previously shown that <jats:italic>H. pylori<\/jats:italic> infection of primary human monocytes increases their potential to respond to subsequent bacterial stimuli \u2013 a process that may be involved in the generation of exaggerated, yet ineffective immune responses directed against the pathogen. In this study, we show that <jats:italic>H. pylori<\/jats:italic>-induced monocyte priming is not a common feature of Gram-negative bacteria, as <jats:italic>Acinetobacter lwoffii<\/jats:italic> induces tolerance to subsequent <jats:italic>Escherichia coli<\/jats:italic> lipopolysaccharide (LPS) challenge. Although the increased reactivity of <jats:italic>H. pylori-<\/jats:italic>infected monocytes seems to be specific to <jats:italic>H. pylori<\/jats:italic>, it appears to be independent of its virulence factors Cag pathogenicity island (CagPAI), cytotoxin associated gene A (CagA), vacuolating toxin A (VacA) and \u03b3-glutamyl transferase (\u03b3-GT). Utilizing whole-cell proteomics complemented with biochemical signaling studies, we show that <jats:italic>H. pylori<\/jats:italic> infection of monocytes induces a unique proteomic signature compared to other pro-inflammatory priming stimuli, namely LPS and the pathobiont <jats:italic>A. lwoffii<\/jats:italic>. Contrary to these tolerance-inducing stimuli, <jats:italic>H. pylori<\/jats:italic> priming leads to accumulation of NF-\u043aB proteins, including p65\/RelA, and thus to the acquisition of a monocyte phenotype more responsive to subsequent LPS challenge. The plasticity of pro-inflammatory responses based on abundance and availability of intracellular signaling molecules may be a heretofore underappreciated form of regulating innate immune memory as well as a novel facet of the pathobiology induced by <jats:italic>H. pylori<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1290833","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T04:32:15Z","timestamp":1700454735000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Helicobacter pylori induces a novel form of innate immune memory via accumulation of NF-\u043aB proteins"],"prefix":"10.3389","volume":"14","author":[{"given":"Tobias","family":"Frauenlob","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Neuper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Regl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Schaepertoens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Unger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Lena","family":"Oswald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieu-Hoa","family":"Dang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian G.","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fritz","family":"Aberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silja","family":"Wessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutta","family":"Horejs-Hoeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,11,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.04.022","article-title":"Global prevalence of helicobacter pylori infection: systematic review and meta-analysis","volume":"153","author":"Hooi","year":"2017","journal-title":"Gastroenterology"},{"key":"B2","article-title":"Humans: Infection with Helicobacter pylori","volume-title":"Schistosomes, Liver Flukes and Helicobacter pylori","year":"1994"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.161042","article-title":"Metagenomic and single-cell RNA-Seq survey of the Helicobacter pylori-infected stomach in asymptomatic individuals","volume":"8","author":"Sorini","year":"2023","journal-title":"JCI Insight"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2013-306253","article-title":"CCL20\/CCR6-mediated migration of regulatory T cells to the Helicobacter pylori-infected human gastric mucosa","volume":"63","author":"Cook","year":"2014","journal-title":"Gut"},{"key":"B5","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1053\/j.gastro.2015.09.004","article-title":"Pathobiology of Helicobacter pylori-induced gastric cancer","volume":"150","author":"Amieva","year":"2016","journal-title":"Gastroenterology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.bj.2015.06.002","article-title":"Helicobacter pylori infection: An overview of bacterial virulence factors and pathogenesis","volume":"39","author":"Kao","year":"2016","journal-title":"BioMed J"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3016","article-title":"Life in the human stomach: persistence strategies of the bacterial pathogen Helicobacter pylori","volume":"11","author":"Salama","year":"2013","journal-title":"Nat Rev Microbiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1186\/s12964-020-00655-1","article-title":"H. pylori modulates DC functions via T4SS\/TNFalpha\/p38-dependent SOCS3 expression","volume":"18","author":"Sarajlic","year":"2020","journal-title":"Cell Commun Signal"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002454","article-title":"Helicobacter pylori versus the host: remodeling of the bacterial outer membrane is required for survival in the gastric mucosa","volume":"7","author":"Cullen","year":"2011","journal-title":"PloS Pathog"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.02.008","article-title":"Helicobacter pylori CagA and gastric cancer: a paradigm for hit-and-run carcinogenesis","volume":"15","author":"Hatakeyama","year":"2014","journal-title":"Cell Host Microbe"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5457.1497","article-title":"Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion","volume":"287","author":"Odenbreit","year":"2000","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1211248110","article-title":"Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance","volume":"110","author":"Oertli","year":"2013","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.02.031","article-title":"Inhibition of T-cell proliferation by Helicobacter pylori gamma-glutamyl transpeptidase","volume":"132","author":"Schmees","year":"2007","journal-title":"Gastroenterology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"B15","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/s41467-022-28407-4","article-title":"The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression","volume":"13","author":"Geller","year":"2022","journal-title":"Nat Commun"},{"key":"B16","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 U.S.A."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2043","article-title":"Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages","volume":"12","author":"Park","year":"2011","journal-title":"Nat Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1016\/j.cell.2022.03.043","article-title":"Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities","volume":"185","author":"Li","year":"2022","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"162","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":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.847958","article-title":"Helicobacter pylori infection of primary human monocytes boosts subsequent immune responses to LPS","volume":"13","author":"Frauenlob","year":"2022","journal-title":"Front Immunol"},{"key":"B21","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":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1511","article-title":"MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification","volume":"26","author":"Cox","year":"2008","journal-title":"Nat Biotechnol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: the universal protein knowledgebase in 2021","volume":"49","author":"UniProt","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3901","article-title":"The Perseus computational platform for comprehensive analysis of (prote)omics data","volume":"13","author":"Tyanova","year":"2016","journal-title":"Nat Methods"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"447268","DOI":"10.1101\/447268","article-title":"A network module for the Perseus software for computational proteomics facilitates proteome interaction graph analysis","author":"Jan","year":"2018","journal-title":"bioRxiv"},{"key":"B27","doi-asserted-by":"publisher","first-page":"060012","DOI":"10.1101\/060012","article-title":"Fast gene set enrichment analysis","author":"Korotkevich","year":"2021","journal-title":"bioRxiv"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1038","article-title":"The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences","volume":"50","author":"Perez-Riverol","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2818.2006.01706.x","article-title":"A guided tour into subcellular colocalization analysis in light microscopy","volume":"224","author":"Bolte","year":"2006","journal-title":"J Microsc"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.03.011","article-title":"Interleukin-10 receptor signaling in innate immune cells regulates mucosal immune tolerance and anti-inflammatory macrophage function","volume":"40","author":"Shouval","year":"2014","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1161\/ATVBAHA.116.308198","article-title":"Monocyte conversion during inflammation and injury","volume":"37","author":"Kratofil","year":"2017","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3189","article-title":"Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection","volume":"19","author":"Grainger","year":"2013","journal-title":"Nat Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.12.015","article-title":"NLRP3 controls the development of gastrointestinal CD11b(+) dendritic cells in the steady state and during chronic bacterial infection","volume":"21","author":"Arnold","year":"2017","journal-title":"Cell Rep"},{"key":"B34","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":"B35","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41581-022-00633-5","article-title":"Trained immunity - basic concepts and contributions to immunopathology","volume":"19","author":"Ochando","year":"2023","journal-title":"Nat Rev Nephrol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3MR0316-118RR","article-title":"Molecular mechanisms of innate memory and tolerance to LPS","volume":"101","author":"Seeley","year":"2017","journal-title":"J Leukoc Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature05836","article-title":"Gene-specific control of inflammation by TLR-induced chromatin modifications","volume":"447","author":"Foster","year":"2007","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111159","article-title":"NF-kappaB memory coordinates transcriptional responses to dynamic inflammatory stimuli","volume":"40","author":"Wang","year":"2022","journal-title":"Cell Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.424390","article-title":"Molecular mechanism responsible for the priming of macrophage activation","volume":"288","author":"Deng","year":"2013","journal-title":"J Biol Chem"},{"key":"B40","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1038\/s41385-022-00528-5","article-title":"Trained immunity of alveolar macrophages requires metabolic rewiring and type 1 interferon signaling","volume":"15","author":"Zahalka","year":"2022","journal-title":"Mucosal Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103060","article-title":"Regulation of TLR2-mediated tolerance and cross-tolerance through IRAK4 modulation by miR-132 and miR-212","volume":"190","author":"Nahid","year":"2013","journal-title":"J Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-013-0616-1","article-title":"Lipopeptides rather than lipopolysaccharide favor the development of dendritic cell dysfunction similar to polymicrobial sepsis in mice","volume":"62","author":"Bruns","year":"2013","journal-title":"Inflammation Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0905815106","article-title":"Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells","volume":"106","author":"Chang","year":"2009","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.10.008","article-title":"Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity","volume":"24","author":"Arts","year":"2016","journal-title":"Cell Metab"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107548","article-title":"The set7 lysine methyltransferase regulates plasticity in oxidative phosphorylation necessary for trained immunity induced by beta-glucan","volume":"31","author":"Keating","year":"2020","journal-title":"Cell Rep"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.11.011","article-title":"Immunometabolic pathways in BCG-induced trained immunity","volume":"17","author":"Arts","year":"2016","journal-title":"Cell Rep"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc0269","article-title":"NF-kappaB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages","volume":"372","author":"Cheng","year":"2021","journal-title":"Science"},{"key":"B48","doi-asserted-by":"publisher","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":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0449-8","article-title":"Allergic inflammatory memory in human respiratory epithelial progenitor cells","volume":"560","author":"Ordovas-Montanes","year":"2018","journal-title":"Nature"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-2566520\/v1","article-title":"Inflammatory memory restrains intestinal stem cell regeneration","author":"Reddy","year":"2023","journal-title":"Res Sq"},{"key":"B51","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1111\/apt.15650","article-title":"Systematic review: gastric microbiota in health and disease","volume":"51","author":"Rajilic-Stojanovic","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0000000000001383","article-title":"Characterization of the gastric microbiota in a pediatric population according to helicobacter pylori status","volume":"36","author":"Llorca","year":"2017","journal-title":"Pediatr Infect Dis J"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-314205","article-title":"Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota","volume":"67","author":"Ferreira","year":"2018","journal-title":"Gut"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1290833\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T04:32:18Z","timestamp":1700454738000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1290833\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,20]]},"references-count":53,"alternative-id":["10.3389\/fimmu.2023.1290833"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1290833","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,20]]},"article-number":"1290833"}}