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bioRxiv · 10.1101/338111

Inhibition of thrombocyte activation restores protective immunity to mycobacterial infection

Hortle, E.·Johnson, K. E.·Johansen, M. D.·Nguyen, T.·Shavit, J. A.·Britton, W. J.·Tobin, D. M.·Oehlers, S. H.
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Abstract

Infection-induced thrombocytosis is a clinically important complication of tuberculosis (TB). Recent studies have separately highlighted a correlation of platelet activation with TB severity and utility of aspirin as a host-directed therapy for TB that modulates the inflammatory response. Here we investigate the possibility that the beneficial effects of aspirin are related to an anti-platelet mode of action. We utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin or platelet-specific glycoprotein IIb/IIIa inhibitors reduced mycobacterial burden demonstrating a detrimental role for infection-induced thrombocyte activation. We found platelet inhibition reduced thrombocyte-macrophage interactions and restored indices of macrophage-mediated immunity to mycobacterial infection. Pathological thrombocyte activation and granuloma formation were found to be intrinsically linked illustrating a bidirectional relationship between host hemostasis and TB pathogenesis. Our study illuminates platelet activation as an efficacious target of anti-platelets drugs including aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.\n\nKey PointsO_LIInhibition of thrombocyte activation improves control of mycobacterial infection.\nC_LIO_LIInhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against mycobacterial infection.\nC_LI

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Hortle, E., Johnson, K. E., Johansen, M. D., Nguyen, T., Shavit, J. A., Britton, W. J., Tobin, D. M., Oehlers, S. H.. 2018-06-04. Inhibition of thrombocyte activation restores protective immunity to mycobacterial infection. https://doi.org/10.1101/338111

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