Abstract
In 2019 10 million people developed symptomatic tuberculosis (TB) disease and 1.2 million died. In active TB the inflammatory response causes tissue destruction, which leads to both acute morbidity and mortality. Tissue destruction in TB is driven by host innate immunity and mediated via enzymes, chiefly matrix metalloproteinases (MMPs) which are secreted by leukocytes and stromal cells and degrade the extracellular matrix. Here we review the growing evidence implicating platelets in TB immunopathology. TB patients typically have high platelet counts, which correlate with disease severity, and a hypercoagulable profile. Platelets are present in human TB granulomas and platelet-associated gene transcripts are increased in TB patients versus healthy controls. Platelets most likely drive TB immunopathology through their effect on other immune cells, particularly monocytes, to lead to upregulation of activation markers, increased MMP secretion, and enhanced phagocytosis. Finally, we consider current evidence supporting use of targeted anti-platelet agents in the treatment of TB due to growing interest in developing host-directed therapies to limit tissue damage and improve treatment outcomes. In summary, platelets are implicated in TB disease and contribute to MMP-mediated tissue damage via their cellular interactions with other leukocytes, and are potential targets for novel host-directed therapies.
Highlights
Tuberculosis (TB) is one of the most important infectious diseases of our time
In a cohort of Peruvian patients with newly diagnosed, drug-sensitive smear-positive pulmonary TB, plasma levels of platelet factor 4 (PF4), platelet-derived growth factor (PDGF)BB, C-C motif chemokine ligand 5 (CCL5; RANTES), matrix metalloproteinases (MMPs)-9, soluble CD40 ligand, and Pentraxin-3 (PTX-3; TNFstimulated gene (TSG)-14) were elevated at baseline compared to age- and sex-matched controls
In a double-blind placebo-controlled study a single dose of oral ticagrelor reduced platelet-monocyte aggregates (PMA) formation in healthy volunteers, and this was associated with an increase in pro-inflammatory cytokines in blood exposed to the TLR2 ligand Pam3CSK4 and a decrease in blood exposed to TLR4 ligand LPS, suggesting that platelets may differentially modulate cytokine responses depending upon the receptors involved [132]
Summary
Tuberculosis (TB) is one of the most important infectious diseases of our time. In 2019 10.0 million people developed symptomatic disease and 1.2 million died, with little change in these figures over the past decade [1]. In a cohort of Peruvian patients with newly diagnosed, drug-sensitive smear-positive pulmonary TB, plasma levels of PF4, platelet-derived growth factor (PDGF)BB, C-C motif chemokine ligand 5 (CCL5; RANTES), MMP-9, soluble CD40 ligand (sCD40L), and Pentraxin-3 (PTX-3; TNFstimulated gene (TSG)-14) were elevated at baseline compared to age- and sex-matched controls Fifty percent of these patients were followed up during their anti-TB treatment, and the plasma concentrations of all of these markers increased at Day 14 and decreased, returning to normal by Day 60 [56]. Activated platelets interact directly with leukocytes to facilitate cellular recruitment towards the site of infection [68] These adhesive interactions can form platelet-monocyte aggregates (PMA) and platelet-neutrophil aggregates (PNA) which lead to cell activation and enhance immune function such as cytokine or MMP production. Ticagrelor and clopidogrel, both P2Y12 inhibitors, given to healthy volunteers significantly reduced inflammatory and prothrombotic
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