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THE PATHOGENESIS OF
STREPTOCOCCAL INFECTIONS: FROM
TOOTH DECAY TO MENINGITIS
Timothy J. Mitchell
The development of bacterial disease has been likened to a molecular arms race, in which the
host tries to eliminate the bacteria, while the bacteria try to survive in the host. Although most
bacteria do not cause disease, some cause serious human infection in a large proportion of
encounters. Between these two extremes are bacteria that can coexist with humans in a carriage
state but, under appropriate circumstances, cause disease. The streptococci exemplify this
group of organisms, and by studying them we can begin to address why bacteria cause such a
wide spectrum of disease.
ENDOCARDITIS
REVIEWS
Diseases
Virulence factors
Streptococcus mutans
Streptococcus agalactiae
Capsule
Laminin-binding protein
- and -proteins
Fibronectin-binding proteins: FbsA, PavA-like protein
C5a-peptidase
Other LPXTG-anchored proteins
Haemolysin (CylE)
Streptococcus pyogenes
Capsule
Fibronectin-binding proteins: SfbI, SfbII, FBP54
(PavA-like), F2, PFBP
C5a-peptidase
Mac
SIC
Haemolysins: SLO, SLS
Pyogenic exotoxins: SpeA, SpeC, SpeG, SpeH,
SpeJ, SpeK, SpeL, SSA, SMEZ, SMEZ2
GRAB
DNAses A, B, C and D
Streptokinase
Hyaluronidase
SpeB (cysteine protease)
Capsule
Cell wall
Pneumolysin
Surface proteins: LPXTG-anchored, choline
anchored (PspA, PspC, autolysin), PavA, PsaA
Hydrogen peroxide
NADH oxidase
Superoxide dismutase
The list of virulence factors is not exhaustive and represents selected examples. FbsA, fibrinogen-binding protein from S. agalactiae;
FBP54, fibronectin-binding protein 54; GRAB, G-related 2-macroglobulin-binding protein; Mac, Mac1-like protein; PavA, pneumococcal
adhesion and virulence A; PFBP, pyogenes fibronectin-binding protein; Psa, pneumococcal surface antigen; Psp, pneumococcal surface
protein; Sfb, streptococccal fibronectin-binding protein; SIC, streptococcal inhibitor of complement; SLO, streptolysin O; SloC, S. mutans
LraI operon C; SLS, streptolysin S; SMEZ, streptococcal mitogenic exotoxin Z; SpaP, streptococcal protein antigen P; Spe, streptococcal
pyogenic exotoxin; SSA, streptococcal superantigen A; WapA, wall-associated protein A.
A signal-transduction system
that consists of a sensor protein
that senses and responds to an
external signal, and which acts
on a response-regulator protein
that transmits the signal to other
components of the cell.
LECTIN
A cell-agglutinating protein of
non-immune origin, which
binds carbohydrates without
modifying them.
PASSIVE IMMUNIZATION
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REVIEWS
Complement
factor H
PavA-like
Secreted: haemolysin
proteases
Glucan-binding
proteins (A and C)
-protein
ABC transporter
Glucan
Fibronectin binding
FbsA
PsaA
Cell-associated
glucosyltransferases
-protein
WapA
GBS
S. mutans
Sucrose
Sortase
Sortase
ABC transporter
Lmb (binds to laminin)
Capsule
PavA-like protein
(fibronectin binding)
Glycolysis
Haemolysin CylE
Acid
SAG
Sugars
C5a peptidase
Sortase
Antigen I/II
Damage
Tooth surface
d
Fibronectin-binding
SfbI
proteins
SfbII
FBP54
MHC
F2
Superantigen
PFBP
C5a
peptidase
TCR
DNAses A, B, C, D
Streptokinase
Hyaluronidase
Cysteine protease (SpeB)
EndoS
GRAB (binds
protease inhibitor)
GAS
Superantigenic
toxins
Capsule
Signal
Sortase
Cytokines
SIC
Mac
interferes with
phagocytosis
Streptococcal
toxic-shock syndrome
Haemolysins
SLO, SLS
cause tissue
damage
and ulcers
M-protein
Binds:
Factor M
Fibronectin
Fibrinogen
Albumin
Choline-binding
proteins
Binds to
factor H, C3
PspC
Binds to polymeric
immunoglobulin
receptor
Sortase
Autolysin
PspA
Pneumolysin
ABC transporter
S. pneumoniae
PsaA
Capsule
Neuraminidase
LPXTG-anchored
proteins
Release of
pneumolysin
by autolysin
PavA
(fibronectin
binding)
Hyaluronidase
Figure 1 | Summary of the main virulence factors of four streptococcal species. a | For Streptococcus mutans, the main causative agent of dental caries, the
main virulence factor is the production of acid as part of the bacterial biofilm that constitutes dental plaque. S. mutans also expresses a variety of cell-surface and
secreted virulence factors, including a haemolysin. b | The polysaccharide capsule has been identified as an important virulence factor for the group B streptococci
(GBS), which are the leading cause of neonatal sepsis, pneumonia and meningitis in the United States and western Europe. GBS also express a variety of surface
proteins that allow evasion of the host immune response, and a haemolysin (CylE), which mediates invasion and tissue damage. c | Group A streptococcus (GAS) is
often termed the most versatile of the streptococcal pathogens, and this is reflected in the huge array of virulence factors that are produced; these allow evasion of
the host immune response and cause tissue damage. Toxins and tissue-degrading enzymes might have an important role in the severe diseases that are associated
with GAS infection, such as necrotizing fasciitis. GAS also produces superantigenic toxins which stimulate T cells to proliferate and produce cytokines, and which
are associated with streptococcal toxic-shock syndrome and the cytotoxins streptolysin O (SLO) and streptolysin S (SLS). d | Streptococcus pneumoniae (the
pneumococcus) is a commensal microorganism of the upper respiratory tract; however, if it gains access to the brain or lower respiratory tract, it can induce massive
inflammation the features of meningitis and pneumonia. Important virulence factors for the pneumococcus include the capsule, choline-binding proteins and a
haemolysin (pneumolysin). ABC, ATP-binding cassette; EndoS, endoglycosidase S; FBP54, fibronectin-binding protein 54; FbsA, fibrinogen-binding protein from
S. agalactiae; Lmb, laminin-binding protein; Mac, Mac1-like protein; MHC, major histocompatibility complex; PavA, pneumococcal adhesion and virulence A; PFBP,
pyogenes fibronectin-binding protein; PsaA, pneumococcal surface antigen A; Psp, pneumococcal surface protein; SAG, salivary agglutinin glycoprotein; Sfb,
streptococcal fibronectin-binding protein; SIC, streptococcal inhibitor of complement; TCR, T-cell receptor; WapA, wall-associated protein A.
SORTASE
the cell surface and show reduced adhesion to salivacoated HYDROXYAPATITE, as well as reduced colonization of
rat teeth in vivo6.
In the presence of sucrose, cell-wall-associated
GLUCOSYLTRANSFERASES mediate the tight attachment of
S. mutans to the tooth surface by synthesizing glucans7.
Glucans interact with surface-associated glucanbinding proteins to promote cellcell aggregation.
Mutation of the genes encoding S. mutans glucosyltransferases and glucan-binding proteins can alter
REVIEWS
GERM-FREE RATS
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REVIEWS
Virulence factor
Streptococcus
mutans
SMU0610
SMU2112
SMU1936
SMU0987
SMU0184
SMU1449
SAG1283
SAG1283
SAG1533
SAG1190
mtsA
fbp
SP1650
SP0966
Streptococcus
agalactiae
Lmb
-protein
-proteins
FbsA
PavA-like protein
C5a-peptidase
Haemolysin (CylE)
SMU1302
SMU1449
SAG1234
SAG0032
SAG0433
SAG1052
SAG1190
SAG0416 (truncated)
SAG0669
lmb
SPy0469
fbp
scpA
SP1002
SP1772
SP0966
Streptococcus
pyogenes
SfbI
SfbII
Fbp54 (PavA-like)
SMU1149
C5a-peptidase
Mac
SIC
Haemolysins:
SLO
SLS
Pyogenic exotoxins:
SpeA, SpeC, SpeG,
SpeH, SpeJ, SpeK,
SpeL, SSA, SMEZ,
SMEZ2
GRAB
DNase
Streptokinase
Hyaluronidase
SAG1190
SAG0416
SpyM3_0098*
SpyM3_0104*
fbp
scpA
SPy0863
sic
SP0966
slo
sagA
SP1923
Superantigens
only present in
S. pyogenes
SAG0788
grab
mf2
ska
hylA
speB
SP0314
Pneumolysin
PspA
PspC
Autolysin
PavA
PsaA
Hydrogen peroxide
NAD oxidase
Superoxide dismutase
Hyaluronidase
SAG1190
SAG1533
SAG0958
SAG0788
SAG1197
slo
fbp
mtsA
nox
sodA
hylA
SP1923
SP0117
SP2190
SP1937
SP0966
SP1650
SP1469
SP0766
SP0314
Streptococcus
pneumoniae
SMU1449
SMU0184
SMU1117
SMU0629
*Best matches are in strain MGA5315, so the gene numbers for this strain are given. FbsA, fibronectin-binding protein from S. agalactiae;
fbp, fibronectin-binding protein; Gbp, glucan-binding protein; GRAB, G-related 2-macroglobulin-binding protein; Lmb, laminin-binding
protein; Mac, Mac1-like protein; PavA, pneumococcal adhesion and virulence A; PFBP, pyogenes fibronectin-binding protein; PsaA,
pneumococcal surface antigen A; Psp, pneumococcal surface protein; Sfb, streptococcal fibronectin-binding protein; SIC, streptococcal
inhibitor of complement; SLO, streptolysin O; SloC, S. mutans LraI operon C; SLS, streptolysin S; SMEZ, streptococcal mitogenic exotoxin Z;
SpaP, streptococcal protein antigen P; Spe, streptococcal pyogenic exotoxin; SSA, streptococcal superantigen A; WapA, wall-associated
protein A.
REVIEWS
a
Bacterial
antigens
Antibody
C3
C4
C1
C4a
C4b
C5
C5 convertase
C3 convertase
C2a C4b
Inflammation
C3a
C2
Bacterium
Bacterium
C5a
C5b
C3b
Bacterium
C1
C3b
C4b
C2b
C2a
C2a
Macrophage
b
C3 convertase
C3
C3b Bb
C5 convertase
Inflammation
C5
C3b Bb C3b
Factor B
C3a
C5b
C3b
Factor D
Bacterium
C5a
Bacterium
Bacterium
Ba
C3b
C3b
Bb
Bb
Macrophage
Figure 2 | The complement system. The complement system can be activated by both the innate and adaptive immune
systems. a | The classical pathway of complement activation, which involves the recognition of bacterial antigens by antibodies.
b | The alternative pathway, which is activated by the binding of complement component C3b to the bacterial surface. In the
classical pathway, the early steps culminate in the formation of the C3 convertase (comprising components C4b and C2a), which
rapidly cleaves C3 into C3a (a chemoattractant) and C3b the main opsonic fragment of the early activation steps which binds
to the bacterial surface. Some C3b also binds to the C3 convertase itself, forming the C5 convertase, which cleaves the C5 into
C5a (which can diffuse away) and C5b, which initiates formation of the membrane-attack complex. In the alternative pathway, a C5
convertase is generated in an antibody-independent manner.
ENDOGLYCOSIDASE
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REVIEWS
MEMBRANE-ATTACK COMPLEX
REVIEWS
EPENDYMAL CILIA
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REVIEWS
Number of genes
References
2,030,921
2,241
21
2603V/R
2,160,267
2,169
146
NEM316
2,211,485
2,387
31
MGAS315
1,900,521
2,085
147
MGAS8232
1,895,017
2,097
140
SF370
1,852,441
1,964
148
SSI-1
1,894,245
1,973
149
TIGR4
2,160,837
2,236
122
R6
2,038,615
2,219
150
S. mutans
UA159
S. agalactiae
S. pyogenes
S. pneumoniae
*Data taken from the Comprehensive Microbial Resource (see Online links).
ENOLASE
The availability of genome sequences has allowed comparisons to be made between species and between strains
at the genomic level. Several strains of the streptococci
described here have been sequenced (TABLE 3). There are
substantial differences between the genome sizes and
total numbers of genes, even for different strains of the
same species. Variation between strains can be large,
especially in a naturally transformable organism such as
S. pneumoniae, and there is a need to understand how
the gene content of a particular strain affects its virulence.
A comparison of the genomes of the four strains of
REVIEWS
b
2,022
1,820
1,618
1,416
1,214
1,013
811
609
407
205
4
432
861
1,290
1,719
2,204
1,984
1,764
1,544
1,324
1,104
884
664
444
2,149
Summary
224
3
861
1,290
1,719
2,149
d
1,886
2,038
432
1,697
1,509
1,321
1,133
945
756
568
380
192
4
432
861
1,290
1,719
2,149
1,834
1,630
1,426
1,222
1,019
815
611
407
203
0
432
864
1,296
1,728
2,160
1.
2.
3.
4.
5.
6.
7.
8.
228
9.
10.
11.
12.
13.
14.
15.
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Online links
DATABASES
The following terms in this article are linked online to:
Entrez: http://www.ncbi.nlm.nih.gov/entrez
CylE | EndoS | FBP54 | FbsA | GRAB | Lmb | M-protein |
pneumolysin | PsaA | PspA | PspC | SLO | SloC | SpaP | SpeB
FURTHER INFORMATION
Comprehensive Microbial Resource:
http://www.tigr.org/tigr-scripts/CMR2/CMRHomePage.spl
Infectious disease information
GAS:
http://www.cdc.gov/ncidod/dbmd/diseaseinfo/groupastreptococ
cal_g.htm
GBS:
http://www.cdc.gov/ncidod/dbmd/diseaseinfo/groupbstrep_g.htm
Streptococcus pneumoniae:
http://www.cdc.gov/ncidod/dbmd/diseaseinfo/streppneum_a.htm
Tim Mitchells web site:
http://www.gla.ac.uk:443/ibls/staff/staff.php?who=159525
Access to this interactive links box is free online.
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