Abstract
Streptococcus (S.) pneumoniae strains vary considerably in their ability to cause invasive disease in humans, which is at least in part determined by the capsular serotype. Platelets have been implicated as sentinel cells in the circulation for host defence. One of their utensils for this function is the expression of Toll-like receptors (TLRs). We here aimed to investigate platelet response to S. pneumoniae and a role for TLRs herein. Platelets were stimulated using four serotypes of S. pneumonia including an unencapsulated mutant strain. In vitro aggregation and flow cytometry assays were performed using blood of healthy volunteers, or blood of TLR knock out and WT mice. For in vivo pneumonia experiments, platelet specific Myd88 knockout (Plt-Myd88-/-) mice were used. We found that platelet aggregation was induced by unencapsulated S. pneumoniae only. Whole blood incubation with all S. pneumoniae serotypes tested resulted in platelet degranulation and platelet-leukocyte complex formation. Platelet activation was TLR independent, as responses were not inhibited by TLR blocking antibodies, not induced by TLR agonists and were equally induced in wild-type and Tlr2-/-, Tlr4-/-, Tlr2/4-/-, Tlr9-/- and Myd88-/- blood. Plt-Myd88-/- and control mice displayed no differences in bacterial clearance or immune response to pneumonia by unencapsulated S. pneumoniae. In conclusion, S. pneumoniae activates platelets through a TLR-independent mechanism that is impeded by the bacterial capsule. Additionally, platelet MyD88-dependent TLR signalling is not involved in host defence to unencapsulated S. pneumoniae in vivo.
Highlights
Streptococcus (S.) pneumoniae is a frequent inhabitant of the upper airways in healthy individuals, and the most common cause of community-acquired pneumonia and a main cause of sepsis [1, 2]
We found that S. pneumoniae activates platelets through a Toll-like receptors (TLRs)-independent mechanism that is impeded by the bacterial capsule and that platelet MyD88-dependent TLR signalling is not involved in host defence to unencapsulated S. pneumoniae in vivo
First we showed that T2.5 is a superior TLR2 blocking antibody compared to other TLR2 antibodies in a whole blood assay (S1 Fig)
Summary
Streptococcus (S.) pneumoniae is a frequent inhabitant of the upper airways in healthy individuals, and the most common cause of community-acquired pneumonia and a main cause of sepsis [1, 2]. Platelets can be activated by pathogens and components thereof during bacterial dissemination [4,5,6,7]. Sepsis patients show an increase in platelet activation markers [8, 9] and a decrease in platelet counts [10, 11], and the extent of these responses is associated with mortality. Platelet activation and Pselectin expression lead to platelet-neutrophil interaction, which recruit neutrophils to an inflammatory site [6, 12] and stimulate the release of neutrophil extracellular traps [6, 13]. Platelet depletion in vivo leads to enhanced bacterial growth and increased mortality during murine S. pneumoniae [14] and Klebsiella pneumoniae [15] induced pneumosepsis
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