The Molecular Basis of Streptococcal Toxic Shock Syndrome
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《新英格兰医药杂志》
Streptococcus pyogenes, also known as group A streptococcus, is the cause of purulent pharyngitis and pyoderma, occasionally complicated by scarlet fever, rheumatic fever, and glomerulonephritis — a scenario familiar to every medical student. Less frequently, group A streptococcus causes deep-tissue infection, bacteremia, and sepsis with vascular collapse and organ failure, a syndrome known as the streptococcal toxic shock syndrome. M protein, a constituent of the streptococcal cell wall, has been known for half a century to be a virulence factor of group A streptococcus, both because it induces a host immune response that contributes to the immunologic complications of streptococcal infection and because the antiphagocytic effect of M protein is important for the establishment and maintenance of the bacterial infection. Now, Herwald et al. have identified a new role for M protein in this type of infection, this time as a major factor in the pathophysiological process of the streptococcal toxic shock syndrome.1
The authors show that M protein can be released from the bacterial surface and then form huge aggregates in blood and tissues because of its ability to bind to fibrinogen, a constituent of blood plasma (Figure 1). They further show that these fibrinogen–M protein aggregates cause substantial damage in an animal model of the streptococcal toxic shock syndrome.
Figure 1. Mechanism of Damage Due to M Protein.
As group A streptococcus invades the blood, M protein is shed from its surface and forms a complex with fibrinogen. A recent study shows that the M protein–fibrinogen complexes bind to integrins on the surface of polymorphonuclear leukocytes, activating these cells.1 Once activated, the polymorphonuclear leukocytes adhere to endothelium and degranulate, releasing a wide variety of hydrolytic enzymes and producing a respiratory burst. The resulting damage to the underlying endothelium leads to vascular leakage and hypercoagulability, which in turn cause the hypotension, disseminated intravascular coagulation, and organ damage that are characteristic of the streptococcal toxic shock syndrome.
To understand how these aggregates cause disease, a little more background information is necessary. The receptors for fibrinogen on leukocytes and platelets in the blood belong to the integrin family. Integrins are surface receptors generally involved in cell adhesion, and they do not normally bind fibrinogen in the blood, because their affinity for monomeric protein is too low. However, when the fibrinogen forms an aggregate with M protein, it becomes an excellent ligand for the integrin receptors. Binding of these integrins on polymorphonuclear leukocytes leads to the activation of the host defense functions of these cells, including the generation of toxic oxygen metabolites and the secretion of a variety of proteolytic and glycolytic enzymes. This response is important for the destruction of invading pathogens but is quite nonspecific in its effect, leading to damage of nearby host tissue as well. This damage to the host contributes substantially to the classic "calor, dolor, and rubor" of inflammation that accompanies local infection and is usually confined to the extravascular tissue where infection occurs.
What happens when these host-defense integrins are engaged on polymorphonuclear leukocytes that have not yet left the bloodstream, as would occur if they encountered aggregates of M protein and fibrinogen created during group A streptococcal bacteremia? In this case, the damage mediated by polymorphonuclear leukocytes is targeted to endothelial cells, leading to vascular leakage and intravascular coagulation, with consequent end-organ damage. If the insult is sufficiently massive, hypotension and vascular collapse ensue. In other words, intravascular activation of polymorphonuclear leukocytes by M protein–fibrinogen aggregates mimics the effects of the streptococcal toxic shock syndrome.
Herwald and colleagues found that intravascular injection of M protein or bacteria expressing M protein can induce these pathophysiological events in a mouse model of disease and that M protein–fibrinogen aggregates are present in a pathological specimen from a patient with the streptococcal toxic shock syndrome. The investigators also blocked the pathologic effects of M protein by injecting a peptide that prevents fibrinogen from interacting with integrin on polymorphonuclear leukocytes.
These findings suggest that activation of polymorphonuclear leukocytes by the M protein–fibrinogen complex is an important component of the pathophysiology of the streptococcal toxic shock syndrome. However, the beneficial effects of the peptide inhibitor may be multifactorial; it also binds fibrinogen and blocks fibrin cross-linking2 — two aspects of coagulation, another important component of systemic inflammation. It should someday be possible to determine the precise role of integrins on polymorphonuclear leukocytes by using monoclonal antibodies or other, more specific inhibitors of their interaction with fibrinogen.
The discovery of the central role of M protein–fibrinogen complexes in the pathogenesis of the streptococcal toxic shock syndrome and the demonstration that the injection of a tetrapeptide inhibitor can ameliorate the syndrome in an animal model point the way to a potential therapeutic intervention in this highly fatal complication of group A streptococcal infection. However, substantial problems have been encountered in attempts to treat sepsis on the basis of an understanding of pathophysiology,3 and blockade of leukocyte integrin has not been effective in trials in patients with ischemia–reperfusion injury.4
From a practical standpoint, it may be quite difficult to block the formation of M protein–fibrinogen complexes or to prevent their activation of polymorphonuclear leukocytes, simply because these events are likely to precede clinical recognition of the streptococcal toxic shock syndrome. Despite this challenge, a more detailed understanding of the pathophysiology of this disease will certainly help optimize therapy, and the work of Herwald et al. should put future investigations on a new and productive path.
Source Information
From the Program in Microbial Pathogenesis and Host Defense, University of California at San Francisco, San Francisco.
References
Herwald H, Cramer H, Morgelin M, et al. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 2004;116:367-379.
Laudano AP, Doolittle RF. Studies on synthetic peptides that bind to fibrinogen and prevent fibrin polymerization: structural requirements, number of binding sites, and species differences. Biochemistry 1980;19:1013-1019.
Lolis E, Bucala R. Therapeutic approaches to innate immunity: severe sepsis and septic shock. Nat Rev Drug Discov 2003;2:635-645.
Harlan JM, Winn RK. Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit Care Med 2002;30:Suppl:S214-S219.(Eric J. Brown, M.D.)
The authors show that M protein can be released from the bacterial surface and then form huge aggregates in blood and tissues because of its ability to bind to fibrinogen, a constituent of blood plasma (Figure 1). They further show that these fibrinogen–M protein aggregates cause substantial damage in an animal model of the streptococcal toxic shock syndrome.
Figure 1. Mechanism of Damage Due to M Protein.
As group A streptococcus invades the blood, M protein is shed from its surface and forms a complex with fibrinogen. A recent study shows that the M protein–fibrinogen complexes bind to integrins on the surface of polymorphonuclear leukocytes, activating these cells.1 Once activated, the polymorphonuclear leukocytes adhere to endothelium and degranulate, releasing a wide variety of hydrolytic enzymes and producing a respiratory burst. The resulting damage to the underlying endothelium leads to vascular leakage and hypercoagulability, which in turn cause the hypotension, disseminated intravascular coagulation, and organ damage that are characteristic of the streptococcal toxic shock syndrome.
To understand how these aggregates cause disease, a little more background information is necessary. The receptors for fibrinogen on leukocytes and platelets in the blood belong to the integrin family. Integrins are surface receptors generally involved in cell adhesion, and they do not normally bind fibrinogen in the blood, because their affinity for monomeric protein is too low. However, when the fibrinogen forms an aggregate with M protein, it becomes an excellent ligand for the integrin receptors. Binding of these integrins on polymorphonuclear leukocytes leads to the activation of the host defense functions of these cells, including the generation of toxic oxygen metabolites and the secretion of a variety of proteolytic and glycolytic enzymes. This response is important for the destruction of invading pathogens but is quite nonspecific in its effect, leading to damage of nearby host tissue as well. This damage to the host contributes substantially to the classic "calor, dolor, and rubor" of inflammation that accompanies local infection and is usually confined to the extravascular tissue where infection occurs.
What happens when these host-defense integrins are engaged on polymorphonuclear leukocytes that have not yet left the bloodstream, as would occur if they encountered aggregates of M protein and fibrinogen created during group A streptococcal bacteremia? In this case, the damage mediated by polymorphonuclear leukocytes is targeted to endothelial cells, leading to vascular leakage and intravascular coagulation, with consequent end-organ damage. If the insult is sufficiently massive, hypotension and vascular collapse ensue. In other words, intravascular activation of polymorphonuclear leukocytes by M protein–fibrinogen aggregates mimics the effects of the streptococcal toxic shock syndrome.
Herwald and colleagues found that intravascular injection of M protein or bacteria expressing M protein can induce these pathophysiological events in a mouse model of disease and that M protein–fibrinogen aggregates are present in a pathological specimen from a patient with the streptococcal toxic shock syndrome. The investigators also blocked the pathologic effects of M protein by injecting a peptide that prevents fibrinogen from interacting with integrin on polymorphonuclear leukocytes.
These findings suggest that activation of polymorphonuclear leukocytes by the M protein–fibrinogen complex is an important component of the pathophysiology of the streptococcal toxic shock syndrome. However, the beneficial effects of the peptide inhibitor may be multifactorial; it also binds fibrinogen and blocks fibrin cross-linking2 — two aspects of coagulation, another important component of systemic inflammation. It should someday be possible to determine the precise role of integrins on polymorphonuclear leukocytes by using monoclonal antibodies or other, more specific inhibitors of their interaction with fibrinogen.
The discovery of the central role of M protein–fibrinogen complexes in the pathogenesis of the streptococcal toxic shock syndrome and the demonstration that the injection of a tetrapeptide inhibitor can ameliorate the syndrome in an animal model point the way to a potential therapeutic intervention in this highly fatal complication of group A streptococcal infection. However, substantial problems have been encountered in attempts to treat sepsis on the basis of an understanding of pathophysiology,3 and blockade of leukocyte integrin has not been effective in trials in patients with ischemia–reperfusion injury.4
From a practical standpoint, it may be quite difficult to block the formation of M protein–fibrinogen complexes or to prevent their activation of polymorphonuclear leukocytes, simply because these events are likely to precede clinical recognition of the streptococcal toxic shock syndrome. Despite this challenge, a more detailed understanding of the pathophysiology of this disease will certainly help optimize therapy, and the work of Herwald et al. should put future investigations on a new and productive path.
Source Information
From the Program in Microbial Pathogenesis and Host Defense, University of California at San Francisco, San Francisco.
References
Herwald H, Cramer H, Morgelin M, et al. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 2004;116:367-379.
Laudano AP, Doolittle RF. Studies on synthetic peptides that bind to fibrinogen and prevent fibrin polymerization: structural requirements, number of binding sites, and species differences. Biochemistry 1980;19:1013-1019.
Lolis E, Bucala R. Therapeutic approaches to innate immunity: severe sepsis and septic shock. Nat Rev Drug Discov 2003;2:635-645.
Harlan JM, Winn RK. Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit Care Med 2002;30:Suppl:S214-S219.(Eric J. Brown, M.D.)