Platelets aggregate in tuberculomas and augment NETs and MMP to worsen TB immunopathology in clinical, murine and in vitro studies

Platelets may worsen tuberculosis (TB) disease by secreting matrix metalloproteinase (MMP) and augmenting neutrophil extracellular traps (NETs). We studied platelet-neutrophil interaction to understand platelet-driven pathology. Murine TB tissues were stained for platelets, NETs and blood vessels. Human and murine tuberculomas and whole blood were analyzed by spatial- and bulk-transcriptomics. 20 tuberculous meningitis (TBM) and 53 non-TBM patients were recruited for plasma cytokine profiling. Human neutrophils and platelets were infected with <italic>M.tb</italic>, NETs assessed by ELISA and staining. Platelet-driven NETs and MMP release pathways were dissected using platelet supernatant and NOX, PAD, PI3K inhibitors. Platelets were found outside blood vessels, accumulating with NETs around tuberculomas, with platelet-related genes upregulated in human and murine tuberculomas. TB patient blood transcriptome was enriched in platelet function genes. TBM patients had higher plasma platelet count than non-TBM patients that associated with increased proinflammatory platelet factors. Addition of platelets to <italic>M.tb</italic>-infected neutrophils augmented NETs in a NOX-independent, PAD-dependent and direct interaction-dependent manner. <italic>M.tb</italic>-induced MMP-1 release from platelets was PI3K-dependent. Platelet-driven NETs and MMP in tuberculomas may worsen TB. Therapies against platelets may improve TB treatment outcomes. <fig><object-id>erj;64/suppl_68/PA641/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>