Scholarlink

<p>By eliciting lung necrosis, which enhances aerosol transmission, <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of <i>Mtb</i>-infected <i>B6.Sst1S</i> mice, we found that lung myeloid cells display elevated senescence markers: cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in <i>Mtb</i>-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed upregulation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in <i>Mtb</i>-infected <i>B6.Sst1S</i> macrophages. As senescent cells are terminally growth-arrested yet metabolically active cells that release tissue-damaging, immunosuppressive SASP, we treated <i>Mtb</i>-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Adjunctive senolytic drug treatment in presence of anti-tuberculosis (TB) therapy prolonged survival and reduced <i>Mtb</i> lung counts in <i>B6.Sst1S</i> and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung pathology and senescence markers. These findings indicate that (1) <i>Mtb</i> infection induce lung myeloid cells to enter a senescent state and that these cells may promote disease progression, and (2) senolytic drugs merit consideration for human clinical trials against TB.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Elimination of senescent cells with senolytic drugs as adjunctive host-directed therapy reduces tuberculosis progression in mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月7日

查看全文
  • Somnath Shee,
  • Yazmin B. Martinez-Martinez,
  • Benjamin Koleske,
  • Moagi Tube Shaku,
  • Shivraj Yabaji,
  • Lester Kobzik,
  • Igor Kramnik,
  • William Bishai

摘要

By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis (Mtb) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers: cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in Mtb-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed upregulation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb-infected B6.Sst1S macrophages. As senescent cells are terminally growth-arrested yet metabolically active cells that release tissue-damaging, immunosuppressive SASP, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Adjunctive senolytic drug treatment in presence of anti-tuberculosis (TB) therapy prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung pathology and senescence markers. These findings indicate that (1) Mtb infection induce lung myeloid cells to enter a senescent state and that these cells may promote disease progression, and (2) senolytic drugs merit consideration for human clinical trials against TB.