{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:31:23Z","timestamp":1772253083788,"version":"3.50.1"},"reference-count":64,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01 AG068568-01A1"],"award-info":[{"award-number":["R01 AG068568-01A1"]}]},{"name":"National Institute of Health","award":["F31 AI169889-01A1"],"award-info":[{"award-number":["F31 AI169889-01A1"]}]},{"name":"National Institute of Health","award":["R01 AG068568-01A1"],"award-info":[{"award-number":["R01 AG068568-01A1"]}]},{"name":"National Institute of Health","award":["F31 AI169889-01A1"],"award-info":[{"award-number":["F31 AI169889-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objective: Neutrophils are essential for vaccine-mediated protection against pneumococcal infection and impairment in their antibacterial function contributes to reduced vaccine efficacy during aging. However, the signaling pathways that control the neutrophil responses in vaccinated hosts are not fully understood. The extracellular adenosine pathway is a known regulator of neutrophils in na\u00efve hosts. The aim of this study was to test the role of this pathway in the function of neutrophils and their protection against infection upon vaccination as a function of the host\u2019s age. Methods: To test the role of adenosine in the antimicrobial activity of neutrophils against antibody-opsonized pneumococci, we used bone marrow-derived neutrophils isolated from wild-type or specific-adenosine-receptors knock-out mice. To measure the effect of adenosine receptor signaling in vivo, we treated vaccinated mice with agonists or antagonists that were specific to the different adenosine receptors prior to pulmonary challenge with pneumococci and assessed the bacterial burden and clinical score post-infection. Results: We found that signaling via the adenosine 2B (A2BR) receptor but not the A2A or A1 receptors diminished the intracellular pneumococcal killing following antibody-mediated uptake in young hosts. In vivo, the agonism of the A2BR receptor significantly worsened the pneumococcal infection outcomes in young, vaccinated mice. In contrast, A2BR signaling had no effect on the intracellular bacterial killing by neutrophils from aged mice. Further, in vivo A2BR inhibition had no effect on the pneumococcal disease progression in aged, vaccinated mice. Conclusions: A2BR signaling reduced pneumococcal vaccine-mediated protection by impairing the antimicrobial activity of neutrophils against antibody-opsonized bacteria in young hosts. However, inhibiting this pathway was not sufficient to boost responses in aged hosts.<\/jats:p>","DOI":"10.3390\/vaccines13040414","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T06:50:27Z","timestamp":1744699827000},"page":"414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Adenosine 2B Receptor Signaling Impairs Vaccine-Mediated Protection Against Pneumococcal Infection in Young Hosts by Blunting Neutrophil Killing of Antibody-Opsonized Bacteria"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2179-3631","authenticated-orcid":false,"given":"Shaunna R.","family":"Simmons","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexsandra P.","family":"Lenhard","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4809-7991","authenticated-orcid":false,"given":"Michael C.","family":"Battaglia","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8936-1341","authenticated-orcid":false,"given":"Elsa N.","family":"Bou Ghanem","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1136\/thoraxjnl-2018-212826","article-title":"Neutrophils in community-acquired pneumonia: Parallels in dysfunction at the extremes of age","volume":"75","author":"Grudzinska","year":"2020","journal-title":"Thorax"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1056\/NEJMoa1500245","article-title":"Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults","volume":"373","author":"Jain","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_3","unstructured":"CDC (2025, February 26). Pneumococcal Disease Surveillance and Trends, Available online: https:\/\/www.cdc.gov\/pneumococcal\/php\/surveillance\/index.html."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s41479-016-0007-9","article-title":"Anatomical site-specific contributions of pneumococcal virulence determinants","volume":"8","author":"Shenoy","year":"2016","journal-title":"Pneumonia"},{"key":"ref_5","unstructured":"Centers for Disease Control and Prevention (2022). Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Network Streptococcus pneumoniae, 2022, Centers for Disease Control and Prevention."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Simmons, S.R., Bhalla, M., Herring, S.E., Tchalla, E.Y.I., and Bou Ghanem, E.N. (2021). Older but Not Wiser: The Age-Driven Changes in Neutrophil Responses during Pulmonary Infections. Infect. Immun., 89.","DOI":"10.1128\/IAI.00653-20"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.mm7401a1","article-title":"Expanded Recommendations for Use of Pneumococcal Conjugate Vaccine Among Adults Aged \u2265 50 Years: Recommendations of the Advisory Committee on Immunization Practices\u2014United States, 2024","volume":"74","author":"Kobayashi","year":"2025","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1056\/NEJMoa1408544","article-title":"Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults","volume":"372","author":"Bonten","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S1473-3099(17)30049-X","article-title":"Serotype-specific effectiveness of 23-valent pneumococcal polysaccharide vaccine against pneumococcal pneumonia in adults aged 65 years or older: A multicentre, prospective, test-negative design study","volume":"17","author":"Suzuki","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1016\/j.vaccine.2010.12.121","article-title":"Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis","volume":"29","author":"Simell","year":"2011","journal-title":"Vaccine"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gingerich, A.D., and Mousa, J.J. (2022). Diverse Mechanisms of Protective Anti-Pneumococcal Antibodies. Front. Cell Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.824788"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Simmons, S.R., Tchalla, E.Y.I., Bhalla, M., and Bou Ghanem, E.N. (2022). The Age-Driven Decline in Neutrophil Function Contributes to the Reduced Efficacy of the Pneumococcal Conjugate Vaccine in Old Hosts. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.849224"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1086\/520200","article-title":"Reduction in functional antibody activity against Streptococcus pneumoniae in vaccinated elderly individuals highly correlates with decreased IgG antibody avidity","volume":"29","author":"Musher","year":"1999","journal-title":"Clin. Infect. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Pechous, R.D. (2017). With Friends Like These: The Complex Role of Neutrophils in the Progression of Severe Pneumonia. Front. Cell Infect. Microbiol., 7.","DOI":"10.3389\/fcimb.2017.00160"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1097\/00001622-200107000-00002","article-title":"The spectrum of pulmonary infections in cancer patients","volume":"13","author":"Rolston","year":"2001","journal-title":"Curr. Opin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/BF01487042","article-title":"The importance of neutrophils in resistance to pneumococcal pneumonia in adult and neonatal mice","volume":"20","author":"Garvy","year":"1996","journal-title":"Inflammation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.it.2003.11.003","article-title":"Adenosine: An endogenous regulator of innate immunity","volume":"25","author":"Cronstein","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1161\/ATVBAHA.111.226845","article-title":"Regulation of neutrophil function by adenosine","volume":"32","author":"Barletta","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12979-024-00442-3","article-title":"Activating A1 adenosine receptor signaling boosts early pulmonary neutrophil recruitment in aged mice in response to Streptococcus pneumoniae infection","volume":"21","author":"Simmons","year":"2024","journal-title":"Immun. Ageing"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bhalla, M., Simmons, S.R., Abamonte, A., Herring, S.E., Roggensack, S.E., and Bou Ghanem, E.N. (2020). Extracellular adenosine signaling reverses the age-driven decline in the ability of neutrophils to kill Streptococcus pneumoniae. Aging Cell, 19.","DOI":"10.1111\/acel.13218"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1016\/j.bcp.2010.02.002","article-title":"Activation of the A(3) adenosine receptor inhibits fMLP-induced Rac activation in mouse bone marrow neutrophils","volume":"79","author":"Gizewski","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1161\/01.RES.0000241428.82502.d4","article-title":"Adenosine inhibits matrix metalloproteinase-9 secretion by neutrophils: Implication of A2a receptor and cAMP\/PKA\/Ca2+ pathway","volume":"99","author":"Ernens","year":"2006","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1164\/rccm.201204-0622OC","article-title":"Adenosine A(2B) receptor deficiency promotes host defenses against gram-negative bacterial pneumonia","volume":"186","author":"Barletta","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Bou Ghanem, E.N., Clark, S., Roggensack, S.E., McIver, S.R., Alcaide, P., Haydon, P.G., and Leong, J.M. (2015). Extracellular Adenosine Protects against Streptococcus pneumoniae Lung Infection by Regulating Pulmonary Neutrophil Recruitment. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005126"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Herring, S.E., Mao, S., Bhalla, M., Tchalla, E.Y.I., Kramer, J.M., and Bou Ghanem, E.N. (2022). Mitochondrial ROS production by neutrophils is required for host antimicrobial function against Streptococcus pneumoniae and is controlled by A2B adenosine receptor signaling. PLoS Pathog., 18.","DOI":"10.1101\/2022.06.26.497688"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Vandendriessche, S., Cambier, S., Proost, P., and Marques, P.E. (2021). Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.624025"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1093\/infdis\/170.3.592","article-title":"Opsonization and antibodies to capsular and cell wall polysaccharides of Streptococcus pneumoniae","volume":"170","author":"Vitharsson","year":"1994","journal-title":"J. Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1189\/jlb.72.6.1092","article-title":"Signal transduction during Fc receptor-mediated phagocytosis","volume":"72","author":"Rosales","year":"2002","journal-title":"J. Leukoc. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1111\/boc.201200013","article-title":"Signalling mechanisms of the leukocyte integrin \u03b1M\u03b22: Current and future perspectives","volume":"104","author":"Lim","year":"2012","journal-title":"Biol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6901","DOI":"10.1073\/pnas.092148299","article-title":"Global changes in gene expression by human polymorphonuclear leukocytes during receptor-mediated phagocytosis: Cell fate is regulated at the level of gene expression","volume":"99","author":"Kobayashi","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Greene, N.G., Narciso, A.R., Filipe, S.R., and Camilli, A. (2015). Peptidoglycan Branched Stem Peptides Contribute to Streptococcus pneumoniae Virulence by Inhibiting Pneumolysin Release. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004996"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1002\/JLB.4MA0120-115RR","article-title":"Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production","volume":"108","author":"Siwapornchai","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Swamydas, M., and Lionakis, M.S. (2013). Isolation, purification and labeling of mouse bone marrow neutrophils for functional studies and adoptive transfer experiments. J. Vis. Exp., 77.","DOI":"10.3791\/50586"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Fante, M.A., Decking, S.M., Bruss, C., Schreml, S., Siska, P.J., Kreutz, M., and Renner, K. (2021). Heat-Inactivation of Human Serum Destroys C1 Inhibitor, Pro-motes Immune Complex Formation, and Improves Human T Cell Function. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052646"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"91","DOI":"10.5625\/lar.2011.27.2.91","article-title":"Difference in Resistance to Streptococcus pneumoniae Infection in Mice","volume":"27","author":"Jeong","year":"2011","journal-title":"Lab. Anim. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.4049\/jimmunol.174.4.1787","article-title":"Cutting edge: Antibody production to pneumococcal polysaccharides requires CD1 molecules and CD8+ T cells","volume":"174","author":"Kobrynski","year":"2005","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.1128\/IAI.00176-10","article-title":"Immune responses to recombinant pneumococcal PsaA antigen delivered by a live attenuated Salmonella vaccine","volume":"78","author":"Wang","year":"2010","journal-title":"Infect. Immun."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Allard, D., Charlebois, R., Gilbert, L., Stagg, J., and Chrobak, P. (2018). CD73-A2a adenosine receptor axis promotes innate B cell antibody responses to pneumococcal polysaccharide vaccination. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191973"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s00441-017-2731-8","article-title":"Armed for destruction: Formation, function and trafficking of neutrophil granules","volume":"371","author":"Yin","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1189\/jlb.0810457","article-title":"Phagosome dynamics during phagocytosis by neutrophils","volume":"90","author":"Nordenfelt","year":"2011","journal-title":"J. Leukoc. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sun, Y., and Huang, P. (2016). Adenosine A2B Receptor: From Cell Biology to Human Diseases. Front. Chem., 4.","DOI":"10.3389\/fchem.2016.00037"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.imlet.2018.04.006","article-title":"Adenosine signaling and the immune system: When a lot could be too much","volume":"205","author":"Antonioli","year":"2019","journal-title":"Immunol. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nri2938","article-title":"Immune cell regulation by autocrine purinergic signalling","volume":"11","author":"Junger","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/S0006-2952(00)00570-0","article-title":"Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells","volume":"61","author":"Fredholm","year":"2001","journal-title":"Biochem. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Nguyen, G.T., Green, E.R., and Mecsas, J. (2017). Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Front. Cell Infect. Microbiol., 7.","DOI":"10.3389\/fcimb.2017.00373"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1152\/physrev.00026.2013","article-title":"Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release","volume":"94","author":"Zorov","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Shekhova, E. (2020). Mitochondrial reactive oxygen species as major effectors of antimicrobial immunity. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008470"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Niyonzima, N., Rahman, J., Kunz, N., West, E.E., Freiwald, T., Desai, J.V., Merle, N.S., Gidon, A., Sporsheim, B., and Lionakis, M.S. (2021). Mitochondrial C5aR1 activity in macrophages controls IL-1\u03b2 production underlying sterile inflammation. Sci. Immunol., 6.","DOI":"10.1126\/sciimmunol.abf2489"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ishii, M., Beeson, G., Beeson, C., and Rohrer, B. (2021). Mitochondrial C3a Receptor Activation in Oxidatively Stressed Epithelial Cells Reduces Mitochondrial Respiration and Metabolism. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.628062"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.it.2007.06.002","article-title":"Neutrophil granules: A library of innate immunity proteins","volume":"28","author":"Borregaard","year":"2007","journal-title":"Trends Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1159\/000353645","article-title":"Role of the cathelicidin-related antimicrobial peptide in inflammation and mortality in a mouse model of bacterial meningitis","volume":"6","author":"Merres","year":"2014","journal-title":"J. Innate Immun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1128\/IAI.00618-13","article-title":"Impaired innate mucosal immunity in aged mice permits prolonged Streptococcus pneumoniae colonization","volume":"81","author":"Krone","year":"2013","journal-title":"Infect. Immun."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Sharma, P., Sharma, N., Mishra, P., Joseph, J., Mishra, D.K., Garg, P., and Roy, S. (2019). Differential Expression of Antimicrobial Peptides in Streptococcus pneumoniae Keratitis and STAT3-Dependent Expression of LL-37 by Streptococcus pneumoniae in Human Corneal Epithelial Cells. Pathogens, 8.","DOI":"10.3390\/pathogens8010031"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.4049\/jimmunol.0900688","article-title":"Human neutrophils kill Streptococcus pneumoniae via serine proteases","volume":"183","author":"Standish","year":"2009","journal-title":"J. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4893","DOI":"10.1128\/IAI.05593-11","article-title":"Cathepsin G and neutrophil elastase play critical and nonredundant roles in lung-protective immunity against Streptococcus pneumoniae in mice","volume":"79","author":"Hahn","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41392-023-01502-8","article-title":"Inflammation and aging: Signaling pathways and intervention therapies","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13054-016-1250-4","article-title":"The role of neutrophils in immune dysfunction during severe inflammation","volume":"20","author":"Leliefeld","year":"2016","journal-title":"Crit. Care"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1532\/IJH97.06141","article-title":"Regulation of neutrophil functions by proinflammatory cytokines","volume":"84","author":"Kato","year":"2006","journal-title":"Int. J. Hematol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41590-020-00845-6","article-title":"Trained immunity, tolerance, priming and differentiation: Distinct immunological processes","volume":"22","author":"Divangahi","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Modestino, L., Tumminelli, M., Mormile, I., Cristinziano, L., Ventrici, A., Trocchia, M., Ferrara, A.L., Palestra, F., Loffredo, S., and Marone, G. (2024). Neutrophil exhaustion and impaired functionality in psoriatic arthritis patients. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1448560"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"5521","DOI":"10.1016\/j.vaccine.2008.07.071","article-title":"Pneumococcal vaccination in older adults induces antibodies with low opsonic capacity and reduced antibody potency","volume":"26","author":"Schenkein","year":"2008","journal-title":"Vaccine"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"623","DOI":"10.4049\/jimmunol.1601686","article-title":"Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination","volume":"198","author":"Schmiel","year":"2017","journal-title":"J. Immunol."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/4\/414\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:14:53Z","timestamp":1760030093000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/4\/414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,15]]},"references-count":64,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["vaccines13040414"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13040414","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.03.18.643957","asserted-by":"object"}]},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,15]]}}}