M protein from Streptococcus pyogenes induces tissue factor expression and pro-coagulant activity in human monocytes

Påhlman, Lisa I.; Malmström, Erik; Mörgelin, Matthias; Herwald, Heiko

doi:10.1099/mic.0.2006/003285-0

Cited by 22 publications

(32 citation statements)

References 39 publications

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“…Serotype-dependent activation of the extrinsic pathway of coagulation has been demonstrated in vitro, with heat-killed serotype M1 and M3, but not serotype M6, GAS strains triggering tissue factor synthesis on isolated human monocytes and cultured human umbilical vein endothelial cells, resulting in subsequent induction of procoagulant activity (373,379). Unlike the activation of the intrinsic pathway, which occurs at the cell surface, the activation of the extrinsic pathway is thought to occur via the interaction of the M protein with TLR2 following the release of M protein from the bacterial cell wall by bacterial or host-derived proteases (380)(381)(382).…”

Section: Dysregulation Of the Coagulation Systemmentioning

confidence: 99%

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

et al. 2014

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SUMMARY Streptococcus pyogenes , also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.

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Section: Dysregulation Of the Coagulation Systemmentioning

confidence: 99%

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

et al. 2014

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“…The release can occur endogenously or by the action of host-derived proteinases (14,15). Once released, M1 protein can cause systemic inflammatory reactions by targeting neutrophils, monocytes, and T cells (14,(16)(17)(18). Interestingly, the interaction of M1 protein with these cells involves different receptors.…”

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confidence: 99%

“…While the interaction with neutrophils is mediated by crosslinking ␤ 2 integrins (14), M1 protein binds to TLR2 on monocytes (16) and to T-cell receptors on T cells (18). These interactions can cause a number of inflammatory reactions, such as the mobilization of heparin binding protein, a potent inducer of vascular leakage and sepsis biomarker (19), and various proinflammatory and Th1-type cytokines (14,(16)(17)(18). Though it has been shown that the release of these proteins contributes to the pathology of an infection, it has not been reported whether the release of M1 protein in proximity to the site of infection can act as a pathogenassociated molecular pattern (PAMP) that helps to alert the innate immune system.…”

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Vigilant Keratinocytes Trigger Pathogen-Associated Molecular Pattern Signaling in Response to Streptococcal M1 Protein

et al. 2015

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The human skin exerts many functions in order to maintain its barrier integrity and protect the host from invading microorganisms. One such pathogen is Streptococcus pyogenes, which can cause a variety of superficial skin wounds that may eventually progress into invasive deep soft tissue infections. Here we show that keratinocytes recognize soluble M1 protein, a streptococcal virulence factor, as a pathogen-associated molecular pattern to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal protein kinase and the subsequent induction and mobilization of the transcription factors NF-B and AP-1. We also determined the imprint of the inflammatory mediators released, such as interleukin-8 (IL-8), growth-related oncogene alpha, migration inhibitory factor, extracellular matrix metalloproteinase inducer, IL-1␣, IL-1 receptor a, and ST2, in response to streptococcal M1 protein. The expression of IL-8 is dependent on Toll-like receptor 2 activity and subsequent activation of the mitogen-activated protein kinases ERK and p38. Notably, this signaling seems to be distinct for IL-8 release, and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate in a proinflammatory manner in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 protein.

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“…The M1 serotype of S. pyogenes is frequently associated with STSS and high mortality (7,15). During infection, S. pyogenes shed M1 protein from their surface, which subsequently triggers activation of neutrophils and monocytes (15,25,26). Although M1 protein challenge is not identical to an infection with whole bacteria, M1 protein is a dominant virulence factor on S. pyogenes, and the M1 serotype of these bacteria is most frequently associated with STSS (7).…”

Section: Discussionmentioning

confidence: 99%

“…addition, the M1 protein has the capacity to induce formation of cytokines (26), chemokines (9), and tissue factor (25), which all contribute to M1 protein-induced edema formation and tissue damage in the lung. Several studies have shown that lung failure is an insidious feature in STSS patients (37,38).…”

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Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

Zhang

Song

Wang

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Zhang S, Song L, Wang Y, Herwald H, Thorlacius H. Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury. Am J Physiol Lung Cell Mol Physiol 305: L756 -L763, 2013. First published September 13, 2013 doi:10.1152/ajplung.00220.2013.-Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung damage. CD162 is an adhesion molecule that has been reported to mediate neutrophil recruitment in acute inflammatory reactions. In this study, the purpose was to investigate the role of CD162 in M1 protein-provoked lung injury. Male C57BL/6 mice were treated with monoclonal antibody directed against CD162 or a control antibody before M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Fluorescence intravital microscopy was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. Inhibition of CD162 reduced M1 proteinprovoked accumulation of neutrophils, edema, and CXC chemokine formation in the lung by Ͼ54%. Moreover, immunoneutralization of CD162 abolished leukocyte rolling and firm adhesion in pulmonary venules of M1 protein-treated animals. In addition, inhibition of CD162 decreased M1 protein-induced capillary trapping of leukocytes in the lung microvasculature and improved microvascular perfusion in the lungs of M1 protein-treated animals. Our findings suggest that CD162 plays an important role in M1 protein-induced lung damage by regulating leukocyte rolling in pulmonary venules. Consequently, inhibition of CD162 attenuates M1 protein-evoked leukocyte adhesion and extravasation in the lung. Thus, our results suggest that targeting the CD162 might pave the way for novel opportunities to protect against pulmonary damage in streptococcal infections. adhesion; chemokines; inflammation and leukocyte CLINICAL MANIFESTATIONS OF Streptococcus pyogenes infections vary from uncomplicated cases to severe and fatal conditions, such as streptococcal toxic shock syndrome (STSS), which is associated with a mortality exceeding 50% (7, 15). Despite significant investigative efforts, management of patients with STSS is largely restricted to antibiotics and supportive care, which is partly due to an incomplete understanding of the basic pathophysiology in STSS. S. pyogenes express several different virulence factors, including M proteins, of which there are more than 80 different serotypes described in the literature (15,26). The M1 serotype of Streptococcus pyogenes is most commonly linked to STSS (7). Numerous studies have documented that M1 protein is a powerful stimulator of innate immune cells, such as monocytes (26) and neutrophils (15). In addition, the M1 protein has the capacity to induce formation of cytokines (26), chemokines (9), and tissue factor (25), which all contribute to M1 protein-induced edema formation and tissue damage in the lung. Several studies have shown that lung failure is an insidious feature in STSS patie...

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M protein from Streptococcus pyogenes induces tissue factor expression and pro-coagulant activity in human monocytes

Cited by 22 publications

References 39 publications

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Vigilant Keratinocytes Trigger Pathogen-Associated Molecular Pattern Signaling in Response to Streptococcal M1 Protein

Targeting CD162 protects against streptococcal M1 protein-evoked neutrophil recruitment and lung injury

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