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

TY - JOUR

T1 - α-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis

AU - Surewaard, Bas G J

AU - Thanabalasuriar, Ajitha

AU - Zeng, Zhutian

AU - Tkaczyk, Christine

AU - Cohen, Taylor S

AU - Bardoel, Bart W

AU - Jorch, Selina K

AU - Deppermann, Carsten

AU - Bubeck Wardenburg, Juliane

AU - Davis, Rachelle P

AU - Jenne, Craig N

AU - Stover, Kendall C

AU - Sellman, Bret R

AU - Kubes, Paul

N1 - Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

PY - 2018/8/8

Y1 - 2018/8/8

N2 - 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.

AB - 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.

KW - ADAM10 Protein/genetics

KW - Amyloid Precursor Protein Secretases/genetics

KW - Animals

KW - Antibodies, Monoclonal/pharmacology

KW - Antibodies, Monoclonal, Humanized

KW - Antibodies, Neutralizing/pharmacology

KW - Bacteremia/physiopathology

KW - Bacterial Toxins/immunology

KW - Broadly Neutralizing Antibodies

KW - Hemolysin Proteins/immunology

KW - Host-Pathogen Interactions/physiology

KW - Humans

KW - Intravital Microscopy/methods

KW - Liver/drug effects

KW - Male

KW - Membrane Proteins/genetics

KW - Mice, Inbred C57BL

KW - Mice, Mutant Strains

KW - Platelet Aggregation/drug effects

KW - Staphylococcal Infections/physiopathology

KW - Staphylococcus aureus/pathogenicity

U2 - 10.1016/j.chom.2018.06.017

DO - 10.1016/j.chom.2018.06.017

M3 - SCORING: Journal article

C2 - 30033122

VL - 24

SP - 271-284.e3

JO - CELL HOST MICROBE

JF - CELL HOST MICROBE

SN - 1931-3128

IS - 2

ER -