PB0762 - Ticagrelor prevents infective endocarditis by mitigating Staphylococcus aureus virulence

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Nicolas Jacques, Bsc

Scientist
Laboratory of Cardiology, GIGA Institute, University of Liège, Liège, Belgium
Liege, Liege, Belgium

Co-Author(s)

SM

Severien Meyers

PhD Candidate
Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium
KL

Kirsten Leeten

PhD student
Laboratory of Cardiology, GIGA Institute, University of Liège, Liège, Belgium
Liege, Liege, Belgium
ML

Marleen Lox

Lab Technician
Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium
MD

Margaux Debuisson

Lab Technician
Laboratory of Cardiology, GIGA Institute, University of Liège, Liège, Belgium
Liege, Liege, Belgium
PD

Philippe Delvenne

Professor
Department of Pathology, CHU of Liège, Liège, Belgium ; Laboratory of Experimental Pathology, GIGA Institute, University of Liège, Liège, Belgium
Liège, Liege, Belgium
AN

Alain Nchimi

MD PhD
Laboratory of Cardiology, GIGA Institute, University of Liège, Liège, Belgium
Liege, Liege, Belgium
MK

Marijke Kuijpers

Associate professor
Maastricht University
Maastricht, Limburg, Netherlands
Thomas Vanassche, MD PhD

MD, PhD
University Hospitals Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium
Kimberly Martinod, PhD

Assistant Professor
Center of Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium
PV

Peter Verhamme, MD, PhD

MD, PhD
University Hospitals Leuven, Belgium
Leuven, Vlaams-Brabant, Belgium
PL

Patrizio Lancellotti

Professor, Medical Doctor
University of Liège Hospital (CHU), Department of Cardiology, Heart Valve Clinic
Liège, Liege, Belgium
CO

Cécile Oury

Research Director; Professor
University of Liège - GIGA - Cardiovascular Sciences
Liège, Liege, Belgium

Background: Infective endocarditis (IE) is a deadly disease mainly caused by the gram-positive and highly virulent bacteria Staphylococcus aureus (SA). Due to lack of efficacy of current antibiotic therapy, there is an urgent need to discover new strategies that could prevent this disease.

Aims: To assess the ability of the antiplatelet drug ticagrelor, which also displays antibacterial activity against gram-positive bacteria, to prevent SAIE.

Methods: We used a mouse model of infective endocarditis induced by a SAIE clinical isolate. Ticagrelor was administered orally at a conventional dosage (3mg/kg, single dose) prior to infection and local histamine infusion on the aortic valve. Infected vegetation presence was determined by Gram staining on heart sections after three days. Antibacterial effect of ticagrelor at dosages equivalent to plasma levels achieved in patients (0.75-1.25mg/L) was assessed in vitro in human blood.

Results: Ticagrelor significantly prevented the formation of infected vegetation, with IE in only 14.3% of ticagrelor-treated mice (n=21) compared to 52.3% of vehicle-treated mice (n=37). Ex vivo ADP-induced platelet aggregation assays confirmed rapid reversibility of antiplatelet activity (4 hours), which made it unlikely that solely the antiplatelet effect would explain IE prevention by ticagrelor. Bacterial survival in blood was not diminished three days post-infection. We therefore assessed whether ticagrelor could affect bacterial virulence. We found that growing SA in the presence of 1.25mg/L ticagrelor inhibited alpha-toxin RNA expression and protein secretion, which was corroborated with drastically reduced hemolysis and platelet aggregation induced by bacterial supernatants. Ticagrelor-treated bacteria could no longer adhered to fibrinogen, and in whole blood perfusion experiments, flow-dependent bacterial adhesion on activated endothelial cells was severely impaired.

Conclusion(s): Our study demonstrates the unprecedented ability of ticagrelor to prevent IE by a novel mechanism of directly mitigating bacterial virulence. Hence, clinical trials using ticagrelor as adjunct therapy to antibiotics in patients at risk for IE are warranted.