Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear <i>Staphylococcus aureus</i> bacteremia
Josh Sun, Satoshi Uchiyama, Joshua Olson, Yosuke Morodomi, Ingrid Cornax, Nao Ando, Yohei Kohno, M.M.T. Kyaw, Bernice Aguilar, Nina M. Haste, Sachiko Kanaji, Taisuke Kanaji, Warren E. Rose, George Sakoulas, Jamey D. Marth, Victor Nizet
Abstract
(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.