Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia.
Repurposed drugs block toxin-driven platelet clearance by the hepatic Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia.
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DOI：
10.1126/scitranslmed.abd6737
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发表时间：
2021-03-24
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
Staphylococcus 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 commonly prescribed drugs as adjunctive therapies to improve patient outcomes. The clinically approved drugs ticagrelor and oseltamivir fortify a regulatory pathway of platelet-mediated immunity to clear staphylococcal bacteremia
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
28.2
作者：
Kaasch, Achim J.;Barlow, Gavin;Edgeworth, Jonathan D.;Fowler, Vance G.;Hellmich, Martin;Hopkins, Susan;Kern, Winfried V.;Llewelyn, Martin J.;Rieg, Siegbert;Rodriguez-Bano, Jesus;Scarborough, Matthew;Seifert, Harald;Soriano, Alex;Tilley, Robert;Torok, M. Estee;Weiss, Verena;Wilson, A. Peter R.;Thwaites, Guy E.
通讯作者：
Thwaites, Guy E.
影响因子：
3.6
作者：
Fitzgerald, JR;Loughman, A;Foster, TJ
通讯作者：
Foster, TJ
DOI：
10.4103/2229-516x.112234
发表时间：
2013-01-01
影响因子：
1.1
作者：
Goel, Divya
通讯作者：
Goel, Divya
影响因子：
20.3
作者：
Jansen, A. J. Gerard;Josefsson, Emma C.;Hoffmeister, Karin M.
通讯作者：
Hoffmeister, Karin M.