Sepsis is a life-threatening complication of infection that involves activation and dysregulation of multiple host immune and coagulation networks. Platelets are circulating blood cells with functional roles at the crossroads of immune and coagulation responses. Thrombocytopenia (decreased platelet count) is an independent predictor of mortality in sepsis, particularly correlated to the development of organ dysfunction. We have investigated platelet activation and immunomodulatory effects during Streptococcus pyogenes infection using flow cytometry, quantitative mass spectrometry-based proteomics and immunofluorescence microscopy.
M1 protein released from the bacterial surface binds plasma fibrinogen and engages the fibrinogen receptor (GPIIb/IIIa) on the platelet surface. Platelet activation occurs only in certain individuals where specific IgG against the M1 protein is also present and engages the FcγRIIA receptor on platelets. We determined that IgG3 and complement C1q are enriched in protein complexes formed by M1 protein in susceptible individuals. This results in C1q deposition and complement activation on M1 protein activated platelets, which is not observed for platelet activation mediated by thrombin generated in the coagulation system. These pathogen-activated platelets were also phagocytosed by monocytes to a higher degree, which may contribute to platelet clearance during active infection.
In subsequent studies we have shown that platelet activation is only mediated by distinct serotypes of S. pyogenes M-proteins that bind fibrinogen. The immunomodulatory effects of platelet activation were further characterized to demonstrate the release of pro-inflammatory proteins (CD40L. PF4, CD62P) and extracellular vesicles (pEVs) from platelet granules and the formation of platelet-leukocyte complexes by M protein stimulated platelets.
Collectively, we report novel insights into platelet immune effector functions during invasive streptococcal disease.