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<p>Influenza A virus (IAV) is a prevalent pathogen that causes severe respiratory infections worldwide. Currently, the incidence of coinfections between IAV and Gram-negative bacteria has been steadily increasing, and the synergistic interaction between IAV infection and bacterial exposure represents a pivotal risk factor for disease exacerbation. Lipopolysaccharide (LPS), a major Gram-negative bacterial virulence factor, is hypothesized to regulate IAV-induced immune response intensity and disease severity by reshaping the pulmonary immune microenvironment. Here, we established an in vivo coadministration model via intratracheal instillation of low-dose LPS and H1N1 to dissect their synergistic pathogenesis. LPS exposure potentiated H1N1-induced severe lung injury, manifested as persistent neutrophil and monocyte infiltration, elevated levels of cytokines (e.g., CXCL1, CCL2, and IL-6), and alveolar damage without affecting viral replication. Mechanistically, LPS triggered immune hyperactivation through early neutrophil recruitment, neutrophil extracellular trap (NET) formation, and a self-sustaining positive feedback loop. Intervention experiments revealed that the degradation of NETs by DNase I or neutrophil inhibition significantly alleviated lung damage and systemic inflammatory responses. This study establishes NET-driven innate immune amplification as a key mechanism underlying LPS-enhanced H1N1 pathogenicity, offers an immunomodulatory approach for severe bacterial-viral coinfections, and underscores the parity of immunomodulatory therapy with anti-infective treatment.</p>

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Exposure to bacterial lipopolysaccharide aggravates H1N1-mediated lung immunopathology via neutrophil extracellular trap formation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月18日

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  • Guiling Yan,
  • Zhongwen Hu,
  • Yuanyuan Peng,
  • Yuqin Tu,
  • Jingling Xie,
  • Yuchao Zhong,
  • Changchun Niu,
  • Yang Luo

摘要

Influenza A virus (IAV) is a prevalent pathogen that causes severe respiratory infections worldwide. Currently, the incidence of coinfections between IAV and Gram-negative bacteria has been steadily increasing, and the synergistic interaction between IAV infection and bacterial exposure represents a pivotal risk factor for disease exacerbation. Lipopolysaccharide (LPS), a major Gram-negative bacterial virulence factor, is hypothesized to regulate IAV-induced immune response intensity and disease severity by reshaping the pulmonary immune microenvironment. Here, we established an in vivo coadministration model via intratracheal instillation of low-dose LPS and H1N1 to dissect their synergistic pathogenesis. LPS exposure potentiated H1N1-induced severe lung injury, manifested as persistent neutrophil and monocyte infiltration, elevated levels of cytokines (e.g., CXCL1, CCL2, and IL-6), and alveolar damage without affecting viral replication. Mechanistically, LPS triggered immune hyperactivation through early neutrophil recruitment, neutrophil extracellular trap (NET) formation, and a self-sustaining positive feedback loop. Intervention experiments revealed that the degradation of NETs by DNase I or neutrophil inhibition significantly alleviated lung damage and systemic inflammatory responses. This study establishes NET-driven innate immune amplification as a key mechanism underlying LPS-enhanced H1N1 pathogenicity, offers an immunomodulatory approach for severe bacterial-viral coinfections, and underscores the parity of immunomodulatory therapy with anti-infective treatment.