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The contribution of the pyruvate metabolic node (SpxB\/LctO pathways) to ST3 pathogenesis is poorly defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated oxygen-dependent fitness, colonization efficiency, and lung pathology in the ST3-strain WU2 and isogenic \u0394\n                      <jats:italic>spxB<\/jats:italic>\n                      , \u0394\n                      <jats:italic>lctO<\/jats:italic>\n                      , and \u0394\n                      <jats:italic>spxB<\/jats:italic>\n                      \u0394\n                      <jats:italic>lctO<\/jats:italic>\n                      mutants.\n                      <jats:italic>In vitro<\/jats:italic>\n                      growth was assessed under nasopharyngeal (21% O\u2082) and alveolar (14% O\u2082) conditions. Murine pneumonia models evaluated survival, bacterial burdens, histopathology, and lung gene expression analyses (RNA-seq and quantitative RT-PCR).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ST3-strain exhibited a unique oxygen-sensitive growth defect at 21% O\u2082, alleviated by\n                      <jats:italic>spxB<\/jats:italic>\n                      deletion, indicating metabolic burden from pyruvate flux. In mice, wild-type WU2 caused severe suppurative bronchopneumonia, alveolar consolidation, hemorrhage, and perivascular inflammation, whereas the \u0394\n                      <jats:italic>spxB<\/jats:italic>\n                      mutant showed enhanced distal lung damage, uncontrolled dissemination, and amplified inflammation. Wild-type infection uniquely induced reorganization of bronchial epithelial membranes, forming prominent bacterium-laden bleb-like structures\u2014host-derived membrane protrusions covering intact pneumococci. These structures appeared to be associated with bacterial translocation into tissue without overt cytotoxicity and were largely absent in\n                      <jats:italic>spxB<\/jats:italic>\n                      -deficient mutants despite comparable bacterial colonization densities in the lung. RNA-seq analysis revealed SpxB-dependent reduced expression of T-cell activation (e.g.,\n                      <jats:italic>Rag1<\/jats:italic>\n                      and\n                      <jats:italic>Themis<\/jats:italic>\n                      ), consistent with immune sequestration via bleb-like structures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The SpxB-dependent pathway contributes to ST3 pathogenesis through metabolic adaptation and is associated with bleb-like structure formation and altered host immune responses in the lung. These bacterium-laden bleb-like structures represent a novel hallmark mechanism in pneumococcal pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12931-026-03776-2","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T15:06:18Z","timestamp":1782140778000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic rewiring at the pyruvate node contributes to severe pneumonia and attenuation of T cell responses in serotype 3 Streptococcus pneumoniae infection"],"prefix":"10.1186","volume":"27","author":[{"given":"Kenichi","family":"Takeshita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana G. 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