On the induction of inflammatory reactions by Streptococcus pyogenes

Sammanfattning: Streptococcus pyogenes is an important human pathogen that causes significant morbidity and mortality worldwide. In order to successfully infect the human host, S. pyogenes is equipped with tools that modulate the human immune defence. The present thesis explores how different streptococcal proteins interfere with innate immunity, adaptive immunity, and blood coagulation. M protein is a surface-bound streptococcal virulence factor with antiphagocytic properties. M proteins can be released from the bacterial surface, and in the present thesis we report that soluble M1 protein is a potent activator of monocytes and T cells. M1 protein-induced monocyte activation involves Toll-like receptor (TLR) 2, and results in secretion of the pro-inflammatory cytokines IL-6, IL-1? and TNF?. In addition, monocytes treated with M1 protein up-regulate Tissue Factor (TF) expression on the cell surface, leading to activation of the extrinsic pathway of coagulation. T cell induction upon M1 protein stimulation results in a potent Th1 type response. Activation does not require normal antigen processing, it is MHC class II dependent, and V? restricted with preferential expansion of V?2 and 4 bearing T cells, suggesting that M1 protein functions as a superantigen. Thrombin activatable fibrinolysis inhibitor (TAFI) is a human procarboxypeptidase circulating in plasma. When activated, TAFI inhibits fibrinolysis and modulates the immune system by cleaving inflammatory mediators such as C5a, fibrinopeptides and bradykinin. Here we find that TAFI binds to Streptococcal collagen-like surface protein A and B on S. pyogenes. These bacteria can also recruit the two TAFI activators thrombin and plasmin to the bacterial surface, leading to the activation of surface-bound TAFI. Taken together, the findings may help explain how S. pyogenes modulates the immune response in order to successfully infect its human host.