{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:46:54Z","timestamp":1782798414528,"version":"3.54.5"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"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. Microbiol."],"abstract":"<jats:p>\n                    <jats:italic>Helicobacter pylori<\/jats:italic>\n                    infection is the leading cause of chronic gastritis and a major risk factor for gastric cancer, yet no licensed vaccine is currently available. The\n                    <jats:italic>H. pylori \u03b3<\/jats:italic>\n                    -glutamyl transferase (hpGGT) is a key virulence factor that contributes to bacterial colonization and persistence, making it a promising antigen for vaccine development. Although hpGGT has been reported to exert immunosuppressive effects through its enzymatic activity, whether the enzymatic activity affects its immunogenicity is unknown. To address this question, we intranasally immunized mice with recombinant wild-type hpGGT (WT-GGT) or a structurally similar, enzymatically inactive variant (In-GGT), each formulated with a liposomal STING-agonist adjuvant. Despite the potential for immunosuppression, the enzymatically active WT-GGT was the superior immunogen: it elicited robust Th1 and Th17 responses, along with strong gastric IgA production\u2014immune features known to be critical for protection against\n                    <jats:italic>H. pylori<\/jats:italic>\n                    . These findings demonstrate that intranasal immunization with WT-GGT combined with a STING-agonist adjuvant induces mucosal and cellular immunity, supporting its potential as a viable vaccine strategy against\n                    <jats:italic>H. pylori<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2026.1825914","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:39:36Z","timestamp":1782797976000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mucosal vaccination with enzymatically active Helicobacter pylori \u03b3-glutamyl transferase (GGT) adjuvanted with STING-agonist elicits robust Th1\/Th17 immunity in mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Monish","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Houston","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Houston","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navin","family":"Varadarajan","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering, University of Houston","place":["Houston, TX, United States"]},{"name":"Department of Biomedical Engineering, University of Houston","place":["Houston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1136\/gut.2007.145839","article-title":"Correlation of T cell response and bacterial clearance in human volunteers challenged with Helicobacter pylori revealed by randomised controlled vaccination with Ty21a-based Salmonella vaccines","volume":"57","author":"Aebischer","year":"2008","journal-title":"Gut"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1006\/cimm.1998.1421","article-title":"Antibody-independent protective mucosal immunity to gastric helicobacter infection in mice","volume":"191","author":"Blanchard","year":"1999","journal-title":"Cell. Immunol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"19029","DOI":"10.1074\/jbc.M603381200","article-title":"Uncoupling the enzymatic and autoprocessing activities of Helicobacter pylori \u03b3-glutamyltranspeptidase","volume":"281","author":"Boanca","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1074\/jbc.M607694200","article-title":"Autoprocessing of Helicobacter pylori \u03b3-glutamyltranspeptidase leads to the formation of a threonine-threonine catalytic dyad","volume":"282","author":"Boanca","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA A Cancer J Clinicians"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1046\/j.1365-2958.1999.01271.x","article-title":"Essential role of Helicobacter pylori \u03b3-glutamyltranspeptidase for the colonization of the gastric mucosa of mice","volume":"31","author":"Chevalier","year":"1999","journal-title":"Mol. Microbiol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.celrep.2015.04.031","article-title":"Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity","volume":"11","author":"Corrales","year":"2015","journal-title":"Cell Rep."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/0264-410x(93)90309-l","article-title":"Protection of germ-free mice from infection by Helicobacter felis after active oral or passive IgA immunization","volume":"11","author":"Czinn","year":"1993","journal-title":"Vaccine"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.1084\/jem.20052442","article-title":"Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis","volume":"203","author":"Delamarre","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e0148514","DOI":"10.1371\/journal.pone.0148514","article-title":"IL-17a and IL-22 induce expression of antimicrobials in gastrointestinal epithelial cells and may contribute to epithelial cell defense against Helicobacter pylori","volume":"11","author":"Dixon","year":"2016","journal-title":"PLoS One"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/s13045-024-01654-2","article-title":"Helicobacter pylori and gastric cancer: mechanisms and new perspectives","volume":"18","author":"Duan","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/ni.1704","article-title":"The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding","volume":"10","author":"Fazilleau","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1128\/IAI.00756-10","article-title":"Proinflammatory cytokine gene expression in the stomach correlates with vaccine-induced protection against Helicobacter pylori infection in mice: an important role for interleukin-17 during the effector phase","volume":"79","author":"Flach","year":"2011","journal-title":"Infect. Immun."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1053\/j.gastro.2024.12.033","article-title":"Eradication therapy to prevent gastric cancer in Helicobacter pylori\u2013positive individuals: systematic review and meta-analysis of randomized controlled trials and observational studies","volume":"169","author":"Ford","year":"2025","journal-title":"Gastroenterology"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"3628","DOI":"10.1128\/IAI.71.6.3628-3633.2003","article-title":"Vaccine-induced protection against Helicobacter pylori in mice lacking both antibodies and interleukin-4","volume":"71","author":"Garhart","year":"2003","journal-title":"Infect. Immun."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"420","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":"ref18","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1186\/s12964-024-01780-x","article-title":"Gamma-glutamyl transferase secreted by Helicobacter pylori promotes the development of gastric cancer by affecting the energy metabolism and histone methylation status of gastric epithelial cells","volume":"22","author":"Jiang","year":"2024","journal-title":"Cell Commun. Signal"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1038\/nsmb.3267","article-title":"Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV","volume":"23","author":"Joyce","year":"2016","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e01029","DOI":"10.1128\/msystems.01029-25","article-title":"Region-specific genomic variation and functional divergence of Helicobacter pylori clinical isolates from the gastric antrum and corpus","volume":"10","author":"Lai","year":"2025","journal-title":"mSystems"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"4629","DOI":"10.1038\/s41467-024-48059-w","article-title":"Universal paramyxovirus vaccine design by stabilizing regions involved in structural transformation of the fusion protein","volume":"15","author":"Langedijk","year":"2024","journal-title":"Nat. Commun."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"6053","DOI":"10.1038\/s41467-024-50234-y","article-title":"An intranasal nanoparticle STING agonist protects against respiratory viruses in animal models","volume":"15","author":"Leekha","year":"2024","journal-title":"Nat. Commun."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1111\/2049-632X.12173","article-title":"Oral immunization with recombinant Lactococcus lactis delivering a multi-epitope antigen CTB-UE attenuates Helicobacter pylori infection in mice","volume":"72","author":"Li","year":"2014","journal-title":"Pathog. Dis."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1620756","DOI":"10.3389\/fcell.2025.1620756","article-title":"Precancerous pathways to gastric cancer: a review of experimental animal models recapitulating the correa cascade","volume":"13","author":"Li","year":"2025","journal-title":"Front. Cell Dev. Biol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/nri3251","article-title":"Recent progress in mucosal vaccine development: potential and limitations","volume":"12","author":"Lycke","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1016\/j.jaci.2015.09.026","article-title":"Fold stability during endolysosomal acidification is a key factor for allergenicity and immunogenicity of the major birch pollen allergen","volume":"137","author":"Machado","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e4792","DOI":"10.1002\/pro.4792","article-title":"UCSF ChimeraX: tools for structure building and analysis","volume":"32","author":"Meng","year":"2023","journal-title":"Protein Sci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"118921","DOI":"10.1016\/j.lfs.2020.118921","article-title":"The gamma-glutamyl transferase gene of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt signal pathway through up-regulating TET1","volume":"267","author":"Meng","year":"2021","journal-title":"Life Sci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/0016-5085(94)90224-0","article-title":"Immunization of BALB\/c mice against Helicobacter felis infection with Helicobacter pylori urease","volume":"107","author":"Michetti","year":"1994","journal-title":"Gastroenterology"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/1478-811X-9-25","article-title":"H. pylori exploits and manipulates innate and adaptive immune cell signaling pathways to establish persistent infection","volume":"9","author":"M\u00fcller","year":"2011","journal-title":"Cell Commun. Signal"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"3047","DOI":"10.1073\/pnas.1211248110","article-title":"Helicobacter pylori \u03b3-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance","volume":"110","author":"Oertli","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"3020","DOI":"10.1038\/s41591-025-03793-6","article-title":"Global lifetime estimates of expected and preventable gastric cancers across 185 countries","volume":"31","author":"Park","year":"2025","journal-title":"Nat. Med."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1002\/ijc.28999","article-title":"Global burden of gastric cancer attributable to Helicobacter pylori: Helicobacter pylori in gastric cancer","volume":"136","author":"Plummer","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1053\/j.gastro.2006.05.001","article-title":"CD25+\/Foxp3+ T cells regulate gastric inflammation and Helicobacter pylori colonization in vivo","volume":"131","author":"Rad","year":"2006","journal-title":"Gastroenterology"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1016\/S0092-8674(00)00179-3","article-title":"The leukotriene C4 transporter MRP1 regulates CCL19 (MIP-3\u03b2, ELC)\u2013dependent mobilization of dendritic cells to lymph nodes","volume":"103","author":"Robbiani","year":"2000","journal-title":"Cell"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.1053\/j.gastro.2018.07.007","article-title":"Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions","volume":"155","author":"Savoldi","year":"2018","journal-title":"Gastroenterology"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1080\/14760584.2017.1306441","article-title":"Influence of protein fold stability on immunogenicity and its implications for vaccine design","volume":"16","author":"Scheiblhofer","year":"2017","journal-title":"Expert Rev. Vaccines"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1820","DOI":"10.1053\/j.gastro.2007.02.031","article-title":"Inhibition of T-cell proliferation by Helicobacter pylori \u03b3-glutamyl transpeptidase","volume":"132","author":"Schmees","year":"2007","journal-title":"Gastroenterology"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1046\/j.1365-2958.2003.03305.x","article-title":"A novel apoptosis-inducing protein from Helicobacter pylori","volume":"47","author":"Shibayama","year":"2003","journal-title":"Mol. Microbiol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1111\/j.1365-2958.2007.05661.x","article-title":"Metabolism of glutamine and glutathione via \u03b3-glutamyltranspeptidase and glutamate transport in Helicobacter pylori: possible significance in the pathophysiology of the organism","volume":"64","author":"Shibayama","year":"2007","journal-title":"Mol. Microbiol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"7295","DOI":"10.1016\/j.vaccine.2018.01.001","article-title":"Status of vaccine research and development for Helicobacter pylori","volume":"37","author":"Sutton","year":"2019","journal-title":"Vaccine"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"3462","DOI":"10.1128\/IAI.01470-06","article-title":"Possible correlates of long-term protection against Helicobacter pylori following systemic or combinations of mucosal and systemic immunizations","volume":"75","author":"Taylor","year":"2007","journal-title":"Infect. Immun."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"50257","DOI":"10.1074\/jbc.M405738200","article-title":"Antigen stability controls antigen presentation","volume":"279","author":"Thai","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"8184","DOI":"10.1038\/s41467-023-43562-y","article-title":"The Helicobacter pylori genome project: insights into H. pylori population structure from analysis of a worldwide collection of complete genomes","volume":"14","author":"Thorell","year":"2023","journal-title":"Nat. Commun."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.cgh.2019.07.045","article-title":"Burden of gastric cancer","volume":"18","author":"Thrift","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.micpath.2017.02.021","article-title":"Surface expression of Helicobacter pylori HpaA adhesion antigen on Vibrio cholerae, enhanced by co-expressed enterotoxigenic Escherichia coli fimbrial antigens","volume":"105","author":"Tobias","year":"2017","journal-title":"Microb. Pathog."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"13636","DOI":"10.1038\/s41598-017-14028-1","article-title":"Helicobacter pylori \u03b3-glutamyl transferase contributes to colonization and differential recruitment of T cells during persistence","volume":"7","author":"W\u00fcstner","year":"2017","journal-title":"Sci. Rep."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"ftv026","DOI":"10.1093\/femspd\/ftv026","article-title":"Protection against Helicobacter pylori infection in BALB\/c mice by oral administration of multi-epitope vaccine of CTB-UreI-UreB","volume":"73","author":"Yang","year":"2015","journal-title":"Pathog. Dis."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1016\/S0140-6736(15)60310-5","article-title":"Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"386","author":"Zeng","year":"2015","journal-title":"Lancet"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"e0130391","DOI":"10.1371\/journal.pone.0130391","article-title":"Immunization with heat shock protein a and \u03b3-Glutamyl Transpeptidase induces reduction on the Helicobacter pylori colonization in mice","volume":"10","author":"Zhang","year":"2015","journal-title":"PLoS One"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1825914\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:39:37Z","timestamp":1782797977000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1825914\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":50,"alternative-id":["10.3389\/fmicb.2026.1825914"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2026.1825914","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]},"article-number":"1825914"}}