PT  - JOURNAL ARTICLE
AU  - Elinor Hortle
AU  - Khelsey E. Johnson
AU  - Matt D. Johansen
AU  - Tuong Nguyen
AU  - Jordan A. Shavit
AU  - Warwick J. Britton
AU  - David M. Tobin
AU  - Stefan H. Oehlers
TI  - Thrombocyte inhibition restores protective immunity to mycobacterial infection in zebrafish
AID  - 10.1101/338111
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 338111
4099  - http://biorxiv.org/content/early/2018/12/01/338111.short
4100  - http://biorxiv.org/content/early/2018/12/01/338111.full
AB  - 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.Key PointsInhibition of thrombocyte activation improves control of mycobacterial infection.Inhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against mycobacterial infection.