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Background <p>Serotype 3 (ST3) <i>Streptococcus pneumoniae</i> remains a major cause of invasive pneumococcal disease and pneumonia despite PCV13 introduction, in part due to potent immune evasion properties. The contribution of the pyruvate metabolic node (SpxB/LctO pathways) to ST3 pathogenesis is poorly defined. </p> Methods <p>We investigated oxygen-dependent fitness, colonization efficiency, and lung pathology in the ST3-strain WU2 and isogenic Δ<i>spxB</i>, Δ<i>lctO</i>, and Δ<i>spxB</i>Δ<i>lctO </i>mutants. <i>In vitro</i> growth was assessed under nasopharyngeal (21% O₂) and alveolar (14% O₂) conditions. Murine pneumonia models evaluated survival, bacterial burdens, histopathology, and lung gene expression analyses (RNA-seq and quantitative RT-PCR). </p> Results <p>ST3-strain exhibited a unique oxygen-sensitive growth defect at 21% O₂, alleviated by <i>spxB</i> deletion, indicating metabolic burden from pyruvate flux. In mice, wild-type WU2 caused severe suppurative bronchopneumonia, alveolar consolidation, hemorrhage, and perivascular inflammation, whereas the Δ<i>spxB</i> 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—host-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 <i>spxB</i>-deficient mutants despite comparable bacterial colonization densities in the lung. RNA-seq analysis revealed SpxB-dependent reduced expression of T-cell activation (e.g., <i>Rag1</i> and <i>Themis</i>), consistent with immune sequestration via bleb-like structures. </p> Conclusions <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.</p>

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Metabolic rewiring at the pyruvate node contributes to severe pneumonia and attenuation of T cell responses in serotype 3 Streptococcus pneumoniae infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Kenichi Takeshita,
  • Ana G. Jop Vidal,
  • Jorge E. Vidal

摘要

Background

Serotype 3 (ST3) Streptococcus pneumoniae remains a major cause of invasive pneumococcal disease and pneumonia despite PCV13 introduction, in part due to potent immune evasion properties. The contribution of the pyruvate metabolic node (SpxB/LctO pathways) to ST3 pathogenesis is poorly defined.

Methods

We investigated oxygen-dependent fitness, colonization efficiency, and lung pathology in the ST3-strain WU2 and isogenic ΔspxB, ΔlctO, and ΔspxBΔlctO mutants. In vitro growth was assessed under nasopharyngeal (21% O₂) and alveolar (14% O₂) conditions. Murine pneumonia models evaluated survival, bacterial burdens, histopathology, and lung gene expression analyses (RNA-seq and quantitative RT-PCR).

Results

ST3-strain exhibited a unique oxygen-sensitive growth defect at 21% O₂, alleviated by spxB deletion, indicating metabolic burden from pyruvate flux. In mice, wild-type WU2 caused severe suppurative bronchopneumonia, alveolar consolidation, hemorrhage, and perivascular inflammation, whereas the ΔspxB 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—host-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 spxB-deficient mutants despite comparable bacterial colonization densities in the lung. RNA-seq analysis revealed SpxB-dependent reduced expression of T-cell activation (e.g., Rag1 and Themis), consistent with immune sequestration via bleb-like structures.

Conclusions

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.