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<p>Despite anti-tuberculous treatment (ATT), central nervous system tuberculosis (CNS-TB) still causes permanent neurological deficits and death. To identify prognostic factors, we profiled a prospective cohort of pediatric HIV-negative tuberculous meningitis (TBM) and non-TBM patients. We found significantly increased cerebrospinal fluid (CSF) matrix metalloproteinases (MMPs) and neutrophil extracellular traps (NETs) in TBM patients with neuroradiological abnormalities and poor outcomes. To dissect mechanisms, we used our existing CNS-TB murine model, which shows neutrophil-rich necrotizing pyogranulomas with MMP-9 and NETs colocalizing, as observed in human CNS-TB pathology. Spatial transcriptomic analysis of both human and murine CNS-TB demonstrates a highly-inflamed and neutrophil-rich microenvironment of inflammatory immune responses, extracellular matrix degradation and angiogenesis within CNS-TB granulomas. Murine CNS-TB treated with ATT and MMP inhibitors SB-3CT or doxycycline show significantly suppressed NETs with improved survival. MMP inhibition arms show attenuated inflammation and well-formed blood vessels within granulomas. Adjunctive doxycycline is highly promising to improve CNS-TB outcomes and survival.</p> Graphical abstract <p></p>

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MMPs and NETs are detrimental in CNS-tuberculosis with MMP Inhibition in CNS-tuberculosis mice improving survival

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月11日

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  • Xuan Ying Poh,
  • Fei Kean Loh,
  • Chen Bai,
  • Hai Tarng Chong,
  • Wei Keat Teo,
  • Yi Hao Wong,
  • Jia Mei Hong,
  • Qing Hao Miow,
  • Pei Min Thong,
  • Bryce Vilaysane,
  • Ting Huey Hu,
  • Srishti Chhabra,
  • Yu Wang,
  • Siew Ching Tiong,
  • Siew Moy Fong,
  • Masako Kamihigashi,
  • Ravisankar Rajarethinam,
  • Wen Donq Looi,
  • Esther Sok Hwee Cheow,
  • Glenn Kunnath Bonney,
  • Leroy Sivappiragasam Pakkiri,
  • Chester Lee Drum,
  • Yan Fen Peng,
  • Ming Lee,
  • Char Loo Tan,
  • Cristine Szu Lyn Ding,
  • Tchoyoson Choie Cheio Lim,
  • Tsin Wen Yeo,
  • Joshua K. Tay,
  • Andres F. Vallejo,
  • Catherine W. M. Ong

摘要

Despite anti-tuberculous treatment (ATT), central nervous system tuberculosis (CNS-TB) still causes permanent neurological deficits and death. To identify prognostic factors, we profiled a prospective cohort of pediatric HIV-negative tuberculous meningitis (TBM) and non-TBM patients. We found significantly increased cerebrospinal fluid (CSF) matrix metalloproteinases (MMPs) and neutrophil extracellular traps (NETs) in TBM patients with neuroradiological abnormalities and poor outcomes. To dissect mechanisms, we used our existing CNS-TB murine model, which shows neutrophil-rich necrotizing pyogranulomas with MMP-9 and NETs colocalizing, as observed in human CNS-TB pathology. Spatial transcriptomic analysis of both human and murine CNS-TB demonstrates a highly-inflamed and neutrophil-rich microenvironment of inflammatory immune responses, extracellular matrix degradation and angiogenesis within CNS-TB granulomas. Murine CNS-TB treated with ATT and MMP inhibitors SB-3CT or doxycycline show significantly suppressed NETs with improved survival. MMP inhibition arms show attenuated inflammation and well-formed blood vessels within granulomas. Adjunctive doxycycline is highly promising to improve CNS-TB outcomes and survival.

Graphical abstract