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Thrombocyte inhibition restores protective immunity to mycobacterial infection in zebrafish

Elinor Hortle, Khelsey E. Johnson, Matt D. Johansen, Tuong Nguyen, Jordan A. Shavit, Warwick J. Britton, View ORCID ProfileDavid M. Tobin, View ORCID ProfileStefan H. Oehlers
doi: https://doi.org/10.1101/338111
Elinor Hortle
1Tuberculosis Research Program, Centenary Institute, University of Sydney, Camperdown, NSW 2050, Australia
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Khelsey E. Johnson
2Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA
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Matt D. Johansen
1Tuberculosis Research Program, Centenary Institute, University of Sydney, Camperdown, NSW 2050, Australia
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Tuong Nguyen
1Tuberculosis Research Program, Centenary Institute, University of Sydney, Camperdown, NSW 2050, Australia
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Jordan A. Shavit
3Department of Pediatrics and Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48107, USA
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Warwick J. Britton
1Tuberculosis Research Program, Centenary Institute, University of Sydney, Camperdown, NSW 2050, Australia
4The University of Sydney, Central Clinical School and Marie Bashir Institute, Camperdown, NSW 2050, Australia
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David M. Tobin
2Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA
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Stefan H. Oehlers
1Tuberculosis Research Program, Centenary Institute, University of Sydney, Camperdown, NSW 2050, Australia
4The University of Sydney, Central Clinical School and Marie Bashir Institute, Camperdown, NSW 2050, Australia
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  • ORCID record for Stefan H. Oehlers
  • For correspondence: stefan.oehlers@sydney.edu.au
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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.

Key Points

  1. Inhibition of thrombocyte activation improves control of mycobacterial infection.

  2. Inhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against mycobacterial infection.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 01, 2018.
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Thrombocyte inhibition restores protective immunity to mycobacterial infection in zebrafish
Elinor Hortle, Khelsey E. Johnson, Matt D. Johansen, Tuong Nguyen, Jordan A. Shavit, Warwick J. Britton, David M. Tobin, Stefan H. Oehlers
bioRxiv 338111; doi: https://doi.org/10.1101/338111
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Thrombocyte inhibition restores protective immunity to mycobacterial infection in zebrafish
Elinor Hortle, Khelsey E. Johnson, Matt D. Johansen, Tuong Nguyen, Jordan A. Shavit, Warwick J. Britton, David M. Tobin, Stefan H. Oehlers
bioRxiv 338111; doi: https://doi.org/10.1101/338111

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