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Objective <p>Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), remains a significant global health burden, characterized by complex host–pathogen interactions that drive heterogeneous clinical outcomes. While pulmonary epithelial cells are increasingly recognized as active participants in innate immunity during <i>Mtb</i> infection, how host defense are altered when the epithelial barrier is compromised remains unclear.</p> Methods <p>In this study, we developed a murine model combining naphthalene-induced pulmonary epithelial injury with <i>Mtb</i> infection and mapped the pulmonary cells landscape through single-cell RNA sequencing (scRNA-seq), followed by in vitro stimulation assays to validate macrophage functional changes.</p> Results <p>Notably, we found a pronounced impairment in pulmonary bacterial clearance. Transcriptomic analysis revealed a widespread suppression of epithelial immune functions and showed that macrophages transitioned from an antimicrobial to an antigen-presenting phenotype, indicating waning pulmonary innate defenses and heightened adaptive immune activation. In vitro experiments further suggested that this macrophage transition may be linked to epithelial cell alterations.</p> Conclusions <p>These findings indicate that pulmonary epithelial integrity may influence early host immune responses to <i>Mycobacterium tuberculosis</i> and provide a transcriptomic framework for exploring epithelial–immune crosstalk as a potential therapeutic target.</p>

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Lung epithelial injury impairs early host immune responses to Mycobacterium tuberculosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • Xuan Miao,
  • Xue Li,
  • Zuokuan He,
  • Guiying Xu,
  • Yu Li,
  • Youwei Wang,
  • Junping Wu,
  • Qi Wu,
  • Huaiyong Chen

摘要

Objective

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health burden, characterized by complex host–pathogen interactions that drive heterogeneous clinical outcomes. While pulmonary epithelial cells are increasingly recognized as active participants in innate immunity during Mtb infection, how host defense are altered when the epithelial barrier is compromised remains unclear.

Methods

In this study, we developed a murine model combining naphthalene-induced pulmonary epithelial injury with Mtb infection and mapped the pulmonary cells landscape through single-cell RNA sequencing (scRNA-seq), followed by in vitro stimulation assays to validate macrophage functional changes.

Results

Notably, we found a pronounced impairment in pulmonary bacterial clearance. Transcriptomic analysis revealed a widespread suppression of epithelial immune functions and showed that macrophages transitioned from an antimicrobial to an antigen-presenting phenotype, indicating waning pulmonary innate defenses and heightened adaptive immune activation. In vitro experiments further suggested that this macrophage transition may be linked to epithelial cell alterations.

Conclusions

These findings indicate that pulmonary epithelial integrity may influence early host immune responses to Mycobacterium tuberculosis and provide a transcriptomic framework for exploring epithelial–immune crosstalk as a potential therapeutic target.