CENTRAL NERVOUS SYSTEM TUBERCULOSIS IMMUNOPATHOLOGY IS DRIVEN BY MATRIX DESTRUCTION WITH MATRIX METALLOPROTEINASES INHIBITION REDUCING INFLAMMATION AND IMPROVING SURVIVAL

Central nervous system tuberculosis (CNS-TB) patients may suffer permanent neurological complications and death despite receiving antituberculous treatment (ATT). Matrix metalloproteinases (MMPs) and neutrophil extracellular traps (NETs) potentially drive tissue destruction in CNS-TB. We aim to determine MMPs, NETs and inflammatory mediators expression in CNS-TB patients and a murine model, and evaluate adjunctive MMP inhibition as host directed therapy. The cerebrospinal fluid (CSF) of 72 TB meningitis (TBM) and non-TBM patients were analysed for MMPs by luminex array and NETs by quantitative fluorometry and ELISA. Four human CNS-TB tissue sections were stained with hematoxylin and eosin for histopathological observation. C57/BL6 Nos2-/- mice were infected intra-cerebroventricularly with H37Rv Mycobacterium tuberculosis (M.tb) and treated with MMP inhibitors SB-3CT or doxycycline with ATT or ATT alone. Brain homogenates were profiled for MMPs, NETs, inflammatory cytokines and chemokines expression. Histopathological evaluation was performed by a pathologist blinded to the treatment received. CNS-TB human and murine histology showed similar necrotising granuloma formation, tissue necrosis and inflammation. MMP-9 expression correlated with NETs concentration and gelatinase activity in CSF of TBM patients (r=0.85, p