Research ArticleBACTEREMIA

Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia

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Science Translational Medicine  24 Mar 2021:
Vol. 13, Issue 586, eabd6737
DOI: 10.1126/scitranslmed.abd6737

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Promoting platelet persistence

Blood infection by Staphylococcus aureus (SA) can be fatal. Sun et al. found that lowered platelet counts associated with mortality in a cohort of patients with bacteremia, and pinpointed SA-induced desialylation and hepatic clearance of platelets as the cause. This reduction in circulating platelets was counteracted by either of two approved drugs, the sialidase inhibitor oseltamivir or ticagrelor, an inhibitor of platelet receptor P2Y12, leading to improved outcomes in a mouse model of SA-induced bacteremia. This study supports the possibility of repurposing two clinically prescribed drugs against bloodstream infection by SA.

Abstract

Staphylococcus aureus (SA) bloodstream infections cause high morbidity and mortality (20 to 30%) despite modern supportive care. In a human bacteremia cohort, we found that 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 after myocardial infarction, blocked α-toxin–mediated platelet injury and resulting thrombocytopenia, thereby 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 commonly prescribed drugs as adjunctive therapies to improve patient outcomes.

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