α‐hemolysin of Staphylococcus aureus impairs thrombus formation

Abstract

Background: Toxins are key virulence determinants of pathogens and can impair the function of host immune cells, including platelets. Insights into pathogen toxin interference with platelets will be pivotal to improve treatment of patients with bacterial bloodstream infections. Materials and Methods: In this study, we deciphered the effects of Staphylococcus aureus toxins α-hemolysin, LukAB, LukDE, and LukSF on human platelets and compared the effects with the pore forming toxin pneumolysin of Streptococcus pneumoniae. Activation of platelets and loss of platelet function were investigated by flow cytometry, aggregometry, platelet viability, fluorescence microscopy, and intracellular calcium release. Thrombus formation was assessed in whole blood.Results: α-hemolysin (Hla) is known to be a pore-forming toxin. Hla-induced calcium influx initially activates platelets as indicated by CD62P and αIIbβ3 integrin activation, but also induces finally alterations in the phenotype of platelets. In contrast to Hla and pneumolysin, S. aureus bicomponent pore-forming leukocidins LukAB, LukED, and LukSF do not bind to platelets and had no significant effect on platelet activation and viability. The presence of small amounts of Hla (0.2 µg/ml) in whole blood abrogates thrombus formation indicating that in systemic infections with S. aureus the stability of formed thrombi is impaired. Damage of platelets by Hla was not neutralized by intravenous immune globulins.

Pneumococcal Neuraminidases Increase Platelet Killing by Pneumolysin

“…IVIG is a blood product containing IgG derived from large plasma pools obtained from thousands of blood donors [52]. It contains anti-PLY antibodies [53] and our data here suggest that IVIG also contains antibodies against pneumococcal neuraminidases (Figure S7). The advantage of IVIG is that it is readily available in most hospitals and that it is inhibiting both, pneumolysin and neuraminidase(s) and probably also targets other pneumococcal proteins [33].…”

Protective Effect of Ticagrelor Against Infective Endocarditis Induced by Virulent Staphylococcus aureus in Mice

“… 11 A recent study indicated that the presence of small amounts of α-toxin in blood abrogates thrombus formation. 31 Thus, limiting α-toxin production to subcytolytic levels might inhibit platelet-dependent vegetation formation. In contrast, at cytolytic concentrations, α-toxin causes aberrant platelet activation and aggregation, as a bacterial immune evasion mechanism.…”

Platelets, Bacterial Adhesins and the Pneumococcus

“…Interactions of platelets with Hla have been reported to cause platelet activation and aggregation [ 98 , 99 ]. In addition, we recently demonstrated that Hla-mediated platelet activation is followed by loss of platelet function, leading to impaired thrombus formation and reduced stability of formed thrombi [ 100 ].…”