Journal Article

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

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

2025

Overview

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

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adolescent / Angiogenesis / Animal models / Animals / Antitubercular Agents - therapeutic use / Biomedical and Life Sciences / Biomedicine / Blood vessels / Central nervous system / Central nervous system diseases / Central nervous system tuberculosis / Cerebrospinal fluid / Child / Child, Preschool / Clinical outcomes / Development and progression / Disease Models, Animal / Doxycycline / Drug therapy / Extracellular matrix / Extracellular Traps - drug effects / Extracellular Traps - metabolism / Extrachromosomal DNA / Female / Gelatinase B / Granulomas / Health aspects / Host-directed therapy / Humans / Hydrocephalus / Immune response / Immunology / Inflammation / Leukocytes (neutrophilic) / Male / Matrix metalloproteinase / Matrix Metalloproteinase Inhibitors - pharmacology / Matrix Metalloproteinase Inhibitors - therapeutic use / Matrix metalloproteinases / Matrix Metalloproteinases - cerebrospinal fluid / Matrix Metalloproteinases - metabolism / Medical imaging / Medical prognosis / Meningitis / Mice / Mice, Inbred C57BL / Microenvironments / Neurobiology / Neuroimaging / Neurological diseases / Neurology / Neurosciences / Neutrophil extracellular trap / Neutrophils / Pathogenesis / Patients / Pediatrics / Protease inhibitors / Proteases / Testing / Thrombosis / Transcriptomics / Tuberculosis / Tuberculosis, Central Nervous System - cerebrospinal fluid / Tuberculosis, Central Nervous System - drug therapy / Tuberculosis, Central Nervous System - metabolism / Tuberculosis, Meningeal - cerebrospinal fluid / Tuberculosis, Meningeal - drug therapy