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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, virulence, and lung pathology in the ST3 strain WU2 and isogenic \u0394\n                    <jats:italic>spxB<\/jats:italic>\n                    , \u0394l\n                    <jats:italic>ctO<\/jats:italic>\n                    , and \u0394\n                    <jats:italic>spxB<\/jats:italic>\n                    \u0394\n                    <jats:italic>lctO<\/jats:italic>\n                    mutants. In vitro growth was assessed under nasopharyngeal (21% O\u2082) and alveolar (14% O\u2082) conditions. Murine pneumonia models evaluated survival, bacterial burdens, histopathology (H&amp;E, confocal microscopy), and lung transcriptomics (RNA-seq).\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 high mortality with severe suppurative bronchopneumonia, alveolar consolidation, hemorrhage, and perivascular inflammation. The \u0394\n                    <jats:italic>spxB<\/jats:italic>\n                    mutant accelerated lethality with enhanced distal lung damage, uncontrolled dissemination, and amplified inflammation. Wild-type infection uniquely induced targeted reorganization of bronchial epithelial membranes, forming prominent bacterium-laden blebs\u2014host-derived membrane protrusions encapsulating intact pneumococci. These novel structures facilitated organized bacterial translocation into tissue without overt cytotoxicity and were largely absent in\n                    <jats:italic>spxB<\/jats:italic>\n                    -deficient mutants despite comparable lung burdens. RNA-seq analysis revealed SpxB-dependent suppression of T cell activation (e.g.,\n                    <jats:italic>Rag1<\/jats:italic>\n                    and\n                    <jats:italic>Themis<\/jats:italic>\n                    ) and acute inflammatory pathways, consistent with immune sequestration via blebs.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The SpxB-dependent pathway orchestrates ST3 virulence by enabling metabolic adaptation and driving bleb-mediated epithelial invasion and immune evasion in the lung. These bacterium-laden blebs represent a novel hallmark mechanism in pneumococcal pathogenesis, offering new insights and potential therapeutic targets.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.13.705843","type":"posted-content","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T03:05:14Z","timestamp":1771211114000},"source":"Crossref","is-referenced-by-count":1,"title":["Metabolic Rewiring at the Pyruvate Node Drives Severe Pneumonia and T-Cell Suppression in Serotype 3\n                  <i>Streptococcus pneumoniae<\/i>\n                  Infection"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-2342","authenticated-orcid":false,"given":"Kenichi","family":"Takeshita","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, Mississippi, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana G.","family":"Jop 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