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The airway epithelial barrier defends against bacteremia and is dependent upon apical junctional complex (AJC) proteins such as E\u2010cadherin. After mouse lung challenge, pneumolysin (PLY), a key\n                    <jats:italic>Sp<\/jats:italic>\n                    virulence factor, stimulates epithelial secretion of an inflammatory eicosanoid, triggering the infiltration of polymorphonuclear leukocytes (PMNs) that secrete high levels of neutrophil elastase (NE), thus promoting epithelial damage and systemic infection. Here, pulmonary E\u2010cadherin staining of intratracheally (\n                    <jats:italic>i.t.<\/jats:italic>\n                    ) inoculated mice revealed PLY\u2010mediated disruption of AJC independently of PMNs. Apical infection of air\u2013liquid interface (ALI) respiratory epithelial monolayers similarly showed that PLY disrupts AJCs. This epithelial damage promoted PMN transmigration and bacterial apical\u2010to\u2010basolateral translocation, and pharmacologically fortifying epithelial barrier function diminished both barrier breach in\u00a0vitro and bacteremia in\u00a0vivo. E\u2010cadherin staining after\n                    <jats:italic>Sp i.t.<\/jats:italic>\n                    inoculation of &gt;\u200920\u2010month\u2010old mice, or apical infection of ALI monolayers derived from these mice, revealed an age\u2010associated vulnerability to PLY\u2010mediated AJC disruption, which in turn enhanced PMN migration and bacteremia. In addition, we found that PMNs from aged mice secrete increased levels of tissue\u2010damaging NE. Simultaneous pharmacological inhibition of tissue\u2010destructive NE and fortification of pulmonary epithelial barrier function was required to reduce the level of\n                    <jats:italic>Sp<\/jats:italic>\n                    bacteremia in aged mice to that of young mice. This work underscores the importance of fully characterizing the multifactorial sources of age\u2010associated susceptibility in devising adjunctive therapies to mitigate invasive pneumococcal disease in the elderly.\n                  <\/jats:p>","DOI":"10.1111\/acel.14474","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T03:35:44Z","timestamp":1736307344000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Weakened Airway Epithelial Junctions and Enhanced Neutrophil Elastase Release Contribute to Age\u2010Dependent Bacteremia Risk Following Pneumococcal Pneumonia"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4572-8663","authenticated-orcid":false,"given":"Shuying","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Microbiology Tufts University School of Medicine  Boston MA USA"},{"name":"Graduate Program in Immunology Tufts Graduate School of Biomedical Sciences  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianmou","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology Tufts University School of Medicine  Boston MA USA"},{"name":"Graduate Program in Immunology Tufts Graduate School of Biomedical Sciences  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Mou","sequence":"additional","affiliation":[{"name":"Mucosal Immunology and Biology Research Center Massachusetts General Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1093-2576","authenticated-orcid":false,"given":"Shumin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology Tufts University School of Medicine  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Leong","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology Tufts University School of Medicine  Boston MA USA"},{"name":"Stuart B Levy Center for the Integrated Management of Antimicrobial Resistance Tufts University  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800748"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2010.0049"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13218"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3109\/15419061.2013.854778"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00280\u201017"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300522"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01488803"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00161"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131219"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12931\u2010016\u20100449\u2010x"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201411\u20101951PP"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2004.07.007"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00023.2002"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.8.4530\u20104538.2005"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2016.01.026"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010015\u20101557\u2010y"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2008.11.009"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2011.04.012"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1473\u20103099(18)30310\u20104"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2024.2330043"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl\u20102017\u2010210074"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12931\u2010022\u201001961\u20107"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02598"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.615959"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10522\u2010015\u20109578\u20108"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.4161\/tisb.24997"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14122619"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010022\u201004150\u2010w"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20100716\u20101460\u20100_17"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00007\u201016"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2001.281.3.G705"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600043"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.49"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005337"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.255653"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.616475"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00048.2013"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1086\/600870"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102249.2004.02611.x"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2020.183237"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201015751\u20106"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281\u2010024\u201001003\u2010y"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00388.2004"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00347.2016"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003727"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.2877"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.35534\/jrbtm.2024.10012"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2011\u20100332OC"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01579\u201006"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1159\/000360165"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0034\u20105687(01)00261\u20104"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2022.865528"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep26321"},{"key":"e_1_2_9_55_1","doi-asserted-by"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