Repurposed Drugs Block Toxin-Driven Platelet Clearance by the Hepatic Ashwell-Morell Receptor to Clear Staphylococcus aureus Bacteremia

Sun, J.; Uchiyama, S.; Olson, J.; Morodomi, Y.; Cornax, I.; Ando, N.; Kohno, Y.; Kyaw, M. M. T.; Aguilar, B.; Haste, N. M.; Kanaji, S.; Kanaji, T.; Rose, W. E.; Sakoulas, G.; Marth, J. D.; Nizet, V.

doi:10.1101/2020.07.06.190322

bioRxiv · 10.1101/2020.07.06.190322

Repurposed Drugs Block Toxin-Driven Platelet Clearance by the Hepatic Ashwell-Morell Receptor to Clear Staphylococcus aureus Bacteremia

Sun, J.·Uchiyama, S.·Olson, J.·Morodomi, Y.·Cornax, I.·Ando, N.·Kohno, Y.·Kyaw, M. M. T.·Aguilar, B.·Haste, N. M.·Kanaji, S.·Kanaji, T.·Rose, W. E.·Sakoulas, G.·Marth, J. D.·Nizet, V.

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Abstract

ABSTRACTStaphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20-30%) despite modern supportive care. In a human bacteremia cohort, development of thrombocytopenia was correlated to increased mortality and increased α-toxin expression by the pathogen. Platelet-derived antibacterial peptides are important in bloodstream defense against SA, but α-toxin decreased platelet viability, induced platelet sialidase to cause desialylation of platelet glycoproteins, and accelerated platelet clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta®), a commonly prescribed P2Y12 receptor inhibitor used post-myocardial infarction, blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thus providing protection from lethal SA infection in a murine intravenous challenge model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet counts and enhanced resistance to SA infection, and the anti-influenza sialidase inhibitor oseltamivir (Tamiflu®) provided similar therapeutic benefit. Thus a “toxin-platelet-AMR” regulatory pathway plays a critical role in the pathogenesis of SA bloodstream infection, and its elucidation provides proof-of-concept for repurposing two FDA-approved drugs as adjunctive therapies to improve patient outcomes.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Sun, J., Uchiyama, S., Olson, J., Morodomi, Y., Cornax, I., Ando, N., Kohno, Y., Kyaw, M. M. T., Aguilar, B., Haste, N. M., Kanaji, S., Kanaji, T., Rose, W. E., Sakoulas, G., Marth, J. D., Nizet, V.. 2020-07-07. Repurposed Drugs Block Toxin-Driven Platelet Clearance by the Hepatic Ashwell-Morell Receptor to Clear Staphylococcus aureus Bacteremia. https://doi.org/10.1101/2020.07.06.190322

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