S. Pyogenes was one of the most common isolates found in the autopsies performed on a number of American soldiers who died from flu in the 1918 pandemic. See this discussion: http://www.flutrackers.com/forum/showthread.php?t=77442
Study:
Streptococcus pyogenes is a major human bacterial pathogen that causes a wide range of infections from common and mostly uncomplicated cases of pharyngitis and impetigo, to severe invasive infections. Since the 1980s an unexplained increased incidence of these severe infections has been reported world-wide, and it is estimated that invasive S. pyogenes infections, streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis, are responsible for more than 150,000 deaths annually.
A potent inflammatory response leading to shock and organ failure is typical of STSS. Previous work has shown that secreted S. pyogenes exotoxins play an important role in STSS by inducing this response. Thus, STSS patients have a propensity to produce high levels of inflammatory cytokines in response to these superantigens. There is also a correlation between the severity of S. pyogenes infection and HLA class II allelic variation, suggesting that the regulation of superantigen-triggered cytokine response contributes to S. pyogenes pathogenicity. Moreover, binding of plasminogen to the bacterium and the subsequent activation to plasmin represents a virulence mechanism that has been proposed to promote the transition from a localized infection into a severe invasive disease. Streptolysin-O-induced platelet/neutrophil aggregation has also been suggested to contribute to the vascular dysfunction in severe S. pyogenes infection.
A key symptom in STSS is a massive vascular leakage (these patients often require 10–20 liters of intravenous fluid per day) leading to hypovolemic hypotension and multiorgan failure. A molecular mechanism contributing to the vascular leakage in STSS has been identified. M protein, a classical virulence determinant of S. pyogenes, is released from the surface of S. pyogenes, forms complexes with fibrinogen that activate neutrophils to secrete Heparin-Binding Protein, HBP (also known as azurocidin or CAP37), a powerful inducer of increased vascular permeability.
The finding that M protein binds fibrinogen was first reported by Kantor et al, and the binding was subsequently mapped to the NH2-terminal half of the protein but excluding the most distal hypervariable region. The proinflammatory effect of M1 protein-fibrinogen complexes was further underlined by a recent and elegant investigation, showing that a mutated form of M1 protein with lower affinity for fibrinogen, lost its capacity to induce HBP release and vascular leakage. In the present work, a marked inter-individual difference was recorded for the M protein-induced HBP release in the blood of healthy individuals. This difference was explained by the presence of specific IgG antibodies against M1 protein, giving rise to protein complexes containing M1 protein, fibrinogen and IgG. Such complexes induce a massive release of HBP by the simultaneous activation of β2 integrins (via fibrinogen) and IgGFc receptors (via IgG bound to M protein in the complexes exposing their Fc regions). The finding that IgG antibodies against a bacterial antigen participate in the induction of a severe and pathologic inflammatory response, represents a novel concept in bacterial virulence.
Results
Individual variation in the M1 protein-induced release of HBP in human blood is due to IgG antibodies
As mentioned, previous work has shown that M1 protein when added to human blood, forms complexes with fibrinogen which activate neutrophils to release HBP. The starting point for this study was the observation that there is a marked individual variation in the response to M1 protein. As shown in Fig. 1A, the blood of some individuals responds with massive HBP release, whereas others are non-responders (defined as a response of less than 10% release of the total amount of HBP).
Unexpectedly, the individuals with powerful responses also had high anti-M1 antibody titers. When serum from a responder was added to the blood of a non-responder together with M1 protein, the serum induced HBP release. However, serum from a non-responder did not. The IgG antibodies in the responder serum were removed by protein G-Sepharose absorption, and this IgG-depleted serum could no longer induce HBP release when added to non-responder blood.
Only IgG from responder serum could, when added to non-responder blood, induce HBP-release in the presence of M1 protein, and following pre-treatment with IdeS, IgG lost its HBP-releasing activity. Taken together the results demonstrate that IgG antibodies are involved in the activation of neutrophils leading to HBP release.
http://www.plospathogens.org/articl...9;jsessionid=96199BBC11DB233805B1D6F65B4544DE
Fredrik Kahn1*, Matthias Mörgelin1, Oonagh Shannon1, Anna Norrby-Teglund2, Heiko Herwald1, Anders I. Olin1, Lars Björck1
1 Department of Clinical Sciences, Division of Infection Medicine, Lund University, BMC, B14, Lund, Sweden, 2 Karolinska Institute, Center for Infection Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
Study:
Streptococcus pyogenes is a major human bacterial pathogen that causes a wide range of infections from common and mostly uncomplicated cases of pharyngitis and impetigo, to severe invasive infections. Since the 1980s an unexplained increased incidence of these severe infections has been reported world-wide, and it is estimated that invasive S. pyogenes infections, streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis, are responsible for more than 150,000 deaths annually.
A potent inflammatory response leading to shock and organ failure is typical of STSS. Previous work has shown that secreted S. pyogenes exotoxins play an important role in STSS by inducing this response. Thus, STSS patients have a propensity to produce high levels of inflammatory cytokines in response to these superantigens. There is also a correlation between the severity of S. pyogenes infection and HLA class II allelic variation, suggesting that the regulation of superantigen-triggered cytokine response contributes to S. pyogenes pathogenicity. Moreover, binding of plasminogen to the bacterium and the subsequent activation to plasmin represents a virulence mechanism that has been proposed to promote the transition from a localized infection into a severe invasive disease. Streptolysin-O-induced platelet/neutrophil aggregation has also been suggested to contribute to the vascular dysfunction in severe S. pyogenes infection.
A key symptom in STSS is a massive vascular leakage (these patients often require 10–20 liters of intravenous fluid per day) leading to hypovolemic hypotension and multiorgan failure. A molecular mechanism contributing to the vascular leakage in STSS has been identified. M protein, a classical virulence determinant of S. pyogenes, is released from the surface of S. pyogenes, forms complexes with fibrinogen that activate neutrophils to secrete Heparin-Binding Protein, HBP (also known as azurocidin or CAP37), a powerful inducer of increased vascular permeability.
The finding that M protein binds fibrinogen was first reported by Kantor et al, and the binding was subsequently mapped to the NH2-terminal half of the protein but excluding the most distal hypervariable region. The proinflammatory effect of M1 protein-fibrinogen complexes was further underlined by a recent and elegant investigation, showing that a mutated form of M1 protein with lower affinity for fibrinogen, lost its capacity to induce HBP release and vascular leakage. In the present work, a marked inter-individual difference was recorded for the M protein-induced HBP release in the blood of healthy individuals. This difference was explained by the presence of specific IgG antibodies against M1 protein, giving rise to protein complexes containing M1 protein, fibrinogen and IgG. Such complexes induce a massive release of HBP by the simultaneous activation of β2 integrins (via fibrinogen) and IgGFc receptors (via IgG bound to M protein in the complexes exposing their Fc regions). The finding that IgG antibodies against a bacterial antigen participate in the induction of a severe and pathologic inflammatory response, represents a novel concept in bacterial virulence.
Results
Individual variation in the M1 protein-induced release of HBP in human blood is due to IgG antibodies
As mentioned, previous work has shown that M1 protein when added to human blood, forms complexes with fibrinogen which activate neutrophils to release HBP. The starting point for this study was the observation that there is a marked individual variation in the response to M1 protein. As shown in Fig. 1A, the blood of some individuals responds with massive HBP release, whereas others are non-responders (defined as a response of less than 10% release of the total amount of HBP).
Unexpectedly, the individuals with powerful responses also had high anti-M1 antibody titers. When serum from a responder was added to the blood of a non-responder together with M1 protein, the serum induced HBP release. However, serum from a non-responder did not. The IgG antibodies in the responder serum were removed by protein G-Sepharose absorption, and this IgG-depleted serum could no longer induce HBP release when added to non-responder blood.
Only IgG from responder serum could, when added to non-responder blood, induce HBP-release in the presence of M1 protein, and following pre-treatment with IdeS, IgG lost its HBP-releasing activity. Taken together the results demonstrate that IgG antibodies are involved in the activation of neutrophils leading to HBP release.
http://www.plospathogens.org/articl...9;jsessionid=96199BBC11DB233805B1D6F65B4544DE
Fredrik Kahn1*, Matthias Mörgelin1, Oonagh Shannon1, Anna Norrby-Teglund2, Heiko Herwald1, Anders I. Olin1, Lars Björck1
1 Department of Clinical Sciences, Division of Infection Medicine, Lund University, BMC, B14, Lund, Sweden, 2 Karolinska Institute, Center for Infection Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden