Severe infections with Streptococcus pyogenes, an important human pathogen, are associated with massive inflammatory reactions in the human host. Here we show that streptococcal M protein interacts with TLR2 on human peripheral blood monocytes. As a consequence, monocytes express the cytokines IL-6, IL-1beta, and TNF-alpha. This response is significantly increased in the presence of neutrophil-derived heparin-binding protein (HBP), which co-stimulates monocytes by interacting with CD11/CD18. Analysis of tissue biopsies from patients with necrotizing fasciitis revealed recruitment of neutrophils and monocytes to the infectious site, combined with the release of HBP. The results show that M protein, in synergy with HBP, evokes an inflammatory response that may contribute to the profound pathophysiological consequences seen in severe streptococcal infections.

Acetic acid is highly effective against Pae-MBL biofilms, and may be used as a simple method to decontaminate sink drains and to prevent nosocomial transmission.

SummaryStreptococcus pyogenes of the M1 serotype is commonly associated with large outbreaks of invasive streptococcal infections and development of streptococcal toxic shock syndrome (STSS). The pathogenesis behind these infections is believed to involve bacterial superantigens that induce potent inflammatory responses, but the reason why strains of the M1 serotype are over-represented in STSS is still not understood. In the present investigation, we show that a highly purified soluble form of the M1 protein from S. pyogenes, which lacks the membranespanning region, is a potent inducer of T cell proliferation and release of Th1 type cytokines. M1 protein-evoked T cell proliferation was HLA class II-dependent but not MHC-restricted, did not require intracellular processing and was Vb-restricted. Extensive mass spectrometry studies indicated that there were no other detectable proteins in the preparation. Taken together, our data demonstrate that soluble M1 protein is a novel streptococcal superantigen, which likely contributes to the excessive T cell activation and hyperinflammatory response seen in severe invasive streptococcal infections.

Regulation of proteolysis is a critical element of the host immune system and plays an important role in the induction of pro-and anti-inflammatory reactions in response to infection. Some bacterial species take advantage of these processes and recruit host proteinases to their surface in order to counteract the host attack. Here we show that Thrombin-activatable Fibrinolysis Inhibitor (TAFI), a zinc-dependent procarboxypeptidase, binds to the surface of group A streptococci of an M41 serotype. The interaction is mediated by the streptococcal collagen-like surface proteins A and B (SclA and SclB), and the streptococcal-associated TAFI is then processed at the bacterial surface via plasmin and thrombin-thrombomodulin. These findings suggest an important role for TAFI in the modulation of host responses by streptococci.Streptococcus pyogenes is an important human Gram-positive pathogen that mainly causes throat and skin infections. Although these conditions are normally superficial and selflimiting, they can occasionally turn into invasive and lifethreatening diseases such as sepsis and necrotizing fasciitis (1). In order to colonize the human host, S. pyogenes expresses socalled adhesins, which allow the bacterium to attach to the extracellular matrix or to cell surface structures. So far, at least 20 adhesins have been described in S. pyogenes, including for instance M proteins and protein F1 (for a review see Ref.2). The two related streptococcal collagen-like surface proteins SclA and SclB, which were first described in 2000 and 2001, also belong to this family (3-7). Although their extracellular parts differ in size and primary sequence, SclA and SclB are organized into a similar "lollipop"-like structure. The stalk is made up of a collagen-like region with varying numbers of GXY repeats, whereas the globular head consists of a non-collagenous amino-terminal variable region. Both proteins have a conserved signal peptide and a carboxyl-terminal region that is attached to the cell wall via an LPATG anchor. The collagen-like regions of Scls have been shown to mediate adhesion to human lung epithelial cells (5) and fibroblasts (4). It has also been reported that SclA from M type 41 activates the collagen receptor ␣ 2 ␤ 1 integrin on fibroblasts (8) and interacts with the low density lipoprotein in human plasma (9).Proteolysis plays an important role in host parasite interactions. Although some immune defense mechanisms such as complement, coagulation, and fibrinolysis are dependent on their activation by limited proteolysis, bacteria have evolved strategies to benefit from these host systems by assembling host proteinases at their surface. Probably the best studied interaction in this respect is the binding of plasmin(ogen) to the bacterial surface, which is thought to be a mechanism for the bacteria to trigger their dissemination in the human host (10).Thrombin-activable fibrinolysis inhibitor (TAFI), 2 also known as procarboxypeptidase B, procarboxypeptidase R, and procarboxypeptidase U, is an arginine-and lysi...