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The

new england journal of

medicine

2093

clinical implications of basic research

The Molecular Basis of Streptococcal Toxic Shock Syndrome

Eric J. Brown, M.D.

Streptococcus pyogenes,

also known as group A strep-tococcus, is the cause of purulent pharyngitis andpyoderma, occasionally complicated by scarlet fe-

ver, rheumatic fever, and glomerulonephritis a scenario familiar to every medical student. Less

frequently, group A streptococcus causes deep-tis-sue infection, bacteremia, and sepsis with vascular

collapse and organ failure, a syndrome known asthe streptococcal toxic shock syndrome. M pro-tein, a constituent of the streptococcal cell wall, has

been known for half a century to be a virulence fac-tor of group A streptococcus, both because it in-

duces a host immune response that contributes tothe immunologic complications of streptococcal

infection and because the antiphagocytic effect ofM protein is important for the establishment andmaintenance of the bacterial infection. Now, Her-

wald et al. have identified a new role for M proteinin this type of infection, this time as a major factor

in the pathophysiological process of the strepto-coccal toxic shock syndrome.

1

The authors show that M protein can be releasedfrom the bacterial surface and then form huge ag-

gregates in blood and tissues because of its abilityto bind to fibrinogen, a constituent of blood plas-ma (Fig. 1). They further show that these fibrino-

genM protein aggregates cause substantial dam-age in an animal model of the streptococcal toxic

shock syndrome.To understand how these aggregates cause dis-

ease, a little more background information is nec-

essary. The receptors for fibrinogen on leukocytesand platelets in the blood belong to the integrin

family. Integrins are surface receptors generally in-volved in cell adhesion, and they do not normally

bind fibrinogen in the blood, because their affinityfor monomeric protein is too low. However, whenthe fibrinogen forms an aggregate with M protein,

it becomes an excellent ligand for the integrin re-ceptors. Binding of these integrins on polymorpho-

nuclear leukocytes leads to the activation of the hostdefense functions of these cells, including the gen-

eration of toxic oxygen metabolites and the secre-

tion of a variety of proteolytic and glycolytic en-zymes. This response is important for the destruc-tion of invading pathogens but is quite nonspecif-

ic in its effect, leading to damage of nearby hosttissue as well. This damage to the host contributes

substantially to the classic calor, dolor, and ruborof inflammation that accompanies local infection

and is usually confined to the extravascular tissuewhere infection occurs.

What happens when these host-defense inte-

grins are engaged on polymorphonuclear leuko-cytes that have not yet left the bloodstream, as would

occur if they encountered aggregates of M proteinand fibrinogen created during group A strepto-

coccal bacteremia? In this case, the damage medi-ated by polymorphonuclear leukocytes is targetedto 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 otherwords, intravascular activation of polymorpho-

nuclear leukocytes by M proteinfibrinogen aggre-gates mimics the effects of the streptococcal toxic

shock syndrome.Herwald and colleagues found that intravas-

cular injection of M protein or bacteria expressing

M protein can induce these pathophysiologicalevents in a mouse model of disease and that M pro-

teinfibrinogen aggregates are present in a patho-logical specimen from a patient with the strepto-coccal toxic shock syndrome. The investigators also

blocked the pathologic effects of M protein by inject-ing a peptide that prevents fibrinogen from inter-

acting with integrin on polymorphonuclear leu-kocytes.

These findings suggest that activation of poly-morphonuclear leukocytes by the M proteinfibrin-ogen complex is an important component of the

pathophysiology of the streptococcal toxic shocksyndrome. However, the beneficial effects of the

peptide inhibitor may be multifactorial; it also bindsfibrinogen and blocks fibrin cross-linking

2

two

aspects of coagulation, another important compo-

The New England Journal of Medicine

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n engl j med 350;20

www.nejm.org may 13, 2004

nent of systemic inflammation. It should someday

be possible to determine the precise role of inte-grins on polymorphonuclear leukocytes by using

monoclonal antibodies or other, more specific in-hibitors of their interaction with fibrinogen.

The discovery of the central role of M proteinfibrinogen complexes in the pathogenesis of the

streptococcal toxic shock syndrome and the dem-onstration that the injection of a tetrapeptide in-hibitor can ameliorate the syndrome in an animal

model point the way to a potential therapeutic in-tervention in this highly fatal complication of

group A streptococcal infection. However, substan-tial problems have been encountered in attempts to

treat sepsis on the basis of an understanding ofpathophysiology,

3

and blockade of leukocyte inte-grin has not been effective in trials in patients with

ischemiareperfusion injury.

4

From a practical standpoint, it may be quite

difficult to block the formation of M proteinfi-brinogen complexes or to prevent their activation

of polymorphonuclear leukocytes, simply because

these events are likely to precede clinical recogni-tion of the streptococcal toxic shock syndrome. De-

spite this challenge, a more detailed understandingof the pathophysiology of this disease will certainly

help optimize therapy, and the work of Herwaldet al. should put future investigations on a new and

productive path.

From the Program in Microbial Pathogenesis and Host Defense,University of California at San Francisco, San Francisco.

1.

Herwald H, Cramer H, Morgelin M, et al. M protein, a classicalbacterial virulence determinant, forms complexes with fibrinogenthat induce vascular leakage. Cell 2004;116:367-79.

2.

Laudano AP, Doolittle RF. Studies on synthetic peptides thatbind to fibrinogen and prevent fibrin polymerization: structuralrequirements, number of binding sites, and species differences.Biochemistry 1980;19:1013-9.

3.

Lolis E, Bucala R. Therapeutic approaches to innate immunity:severe sepsis and septic shock. Nat Rev Drug Discov 2003;2:635-45.

4.

Harlan JM, Winn RK. Leukocyte-endothelial interactions: clini-cal trials of anti-adhesion therapy. Crit Care Med 2002;30:Suppl:S214-S219.

Copyright 2004 Massachusetts Medical Society.

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 proteinfibrinogen complexes bind to integrins on the surface of polymorphonuclear

leukocytes, activating these cells.

1

Once activated, the polymorphonuclear leukocytes adhere to endothelium and degran-

ulate, releasing a wide variety of hydrolytic enzymes and producing a respiratory burst. The resulting damage to theunderlying endothelium leads to vascular leakage and hypercoagulability, which in turn cause the hypotension, dis-

seminated intravascular coagulation, and organ damage that are characteristic of the streptococcal toxic shock syndrome.

Fibrinogen

M proteinfibrinogen aggregate

M proteinfibrinogenaggregate

Endothelium

Polymorphonuclearolymorphonuclearleukocyteeukocyte

Vascular smoothascular smoothmuscleuscleVascular smoothmuscle

Polymorphonuclearleukocyte

M proteinGroup Astreptococci

A

M protein releasedfrom bacterial

surface

Degranulation

Respiratory burst

Endothelial damage

B

The New England Journal of Medicine

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Copyright 2004 Massachusetts Medical Society. All rights reserved.