α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

Bas G.J. Surewaard, Ajitha Thanabalasuriar, Zhutian Zeng, Christine Tkaczyk, Taylor S. Cohen, Bart W. Bardoel, Selina K. Jorch, Carsten Deppermann, Juliane Bubeck Wardenburg, Rachelle P. Davis, Craig N. Jenne, Kendall C. Stover, Bret R. Sellman, Paul Kubes

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

During sepsis, small blood vessels can become occluded by large platelet aggregates of poorly understood etiology. During Staphylococcal aureus infection, sepsis severity is linked to the bacterial α-toxin (α-hemolysin, AT) through unclear mechanisms. In this study, we visualized intravascular events in the microcirculation and found that intravenous AT injection induces rapid platelet aggregation, forming dynamic micro-thrombi in the microcirculation. These aggregates are retained in the liver sinusoids and kidney glomeruli, causing multi-organ dysfunction. Acute staphylococcal infection results in sequestration of most bacteria by liver macrophages. Platelets are initially recruited to these macrophages and help eradicate S. aureus. However, at later time points, AT causes aberrant and damaging thrombosis throughout the liver. Treatment with an AT neutralizing antibody (MEDI4893) prevents platelet aggregation and subsequent liver damage, without affecting the initial and beneficial platelet recruitment. Thus, AT neutralization may represent a promising approach to combat staphylococcal-induced intravascular coagulation and organ dysfunction. Staphylococcal sepsis often results in thrombocytopenia and multi-organ dysfunction. Using intravital imaging, Surewaard et al. discovered that α-toxin (AT) directly targets platelets, resulting in detrimental aggregation in the circulation. Neutralizing AT during staphylococcal sepsis does not interfere with beneficial platelet responses, while preventing microvascular dysfunction and thrombosis.

Original languageEnglish
Pages (from-to)271-284.e3
JournalCell Host and Microbe
Volume24
Issue number2
DOIs
StatePublished - Aug 8 2018

Keywords

  • Kupffer cells
  • MRSA
  • Staphylococcus aureus
  • alpha toxin
  • antibiotic resistance
  • coagulation
  • platelets
  • sepsis

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