Group A Streptococcus: Host Aspect

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INFECTIOUS DISEASES
Group A Streptococcus Host Aspect Yee-Shin Lin,
Ph.D. December 19, 2007
Outlines Introduction Pathogenesis and host
responses Host-streptococcus
interactions Innate immune responses
Induction of inflammation and apoptosis
Autoimmunity post-infectious sequelae
Autophagy Vaccinology
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Introduction
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A wide spectrum of diseases in humans
Mild illness pharyngitis / tonsillitis / otitis
media / impetigo / scarlet fever Severe illness
necrotizing fasciitis / bacteremia /
streptococcal toxic shock syndrome
(STSS) Post-streptococcal sequelae acute
glomerulonephritis / rheumatic fever / reactive
arthritis
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Pathogenesis and host responses
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Host-streptococcus interactions
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Effect of lactoferrin on up-regulation of
expression of streptococcal pyrogenic exotoxin
(Spe) A.
Ability of HL-1 medium or its fraction with
proteins ?10 kDa to induce up-regulation of
expression of streptococcal pyrogenic exotoxin
(Spe) A and down-regulation of expression of
SpeB.
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Graham et al. Group A Streptococcus transcriptome
dynamics during growth in human blood reveals
bacterial adaptive and survival strategies. Am J
Pathol 2005, 166456-465. Shelburne et al.
Growth characteristics of and virulence factor
production by group A Streptococcus during
cultivation in human saliva. Infect Immun 2005,
734723-4731. Graham et al. Analysis of the
transcriptome of group A Streptococcus in mouse
soft tissue infection. Am J Pathol 2006,
169927-942.
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Innate immune responses
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J. Allergy Clin. Immunol., 200712013-22
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• Inhibition of PMN recruitment and phagocytosis
  (I)
• C5a peptidase (ScpA)
• Inhibit PMN recruitment
• IL-8 protease (ScpC) (Scp streptococcal
  chemokine protease)
• Inhibit PMN recruitment
• M and M-like proteins
• Bind to complement-regulating proteins
  (such as C4bp, factor H) and other
• plasma proteins (such as fibrinogen) ()
• Inhibit C3b-mediated PMN binding
• Help to survive inside PMN or in NET ()
• Streptococcal inhibitor of complement Sic
• Bind to C5b-C7 to inhibit the formation of
  membrane attack complex
• (MAC)
• Bind to ezrin and alter PMN cytoskeleton
  function to inhibit phagocytosis
• Inactivate antibacterial peptides

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• Inhibition of PMN recruitment and phagocytosis
  (II)
• IdeS/CD11b homolog Mac (cysteine protease)
• Bind to FcR and cleave IgG to inhibit PMN
  phagocytosis and killing
• SpeB (cysteine protease)
• Release C5a peptidase from the surface of
  GAS
• Cleave IgG and properdin to inhibit
  opsonophagocytosis
• EndoS (endoglycosidase)
• Hydrolyze the conserved asparagine-linked
  glycan on IgG to inhibit IgG-
• mediated opsonophagocytosis
• Hyaluronic acid capsule
• Act as a physical barrier to prohibit
  interaction of PMN with opsonins on
• bacterial surface

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Fig. 7. Working model for the inhibition of
complement deposition by M proteins. Complement
is activated via the classical pathway by S.
pyogenes, potentially resulting in surface
deposition of C3b. However, M protein (a dimeric
coiled-coil protein) inhibits this deposition of
C3b by recruiting a human plasma protein, which
acts by reducing the formation or activity of the
classical pathway C3 convertase. Some M proteins,
such as M5, bind fibrinogen (Fg), while other M
proteins, such as M22, recruit the 570 kDa
C4b-binding protein (C4BP), an inhibitor of the
classical pathway. Importantly, the inhibition of
complement deposition promotes resistance to
phagocytosis. As indicated, the M22 protein (and
many other M proteins) also binds IgA, which
contributes to phagocytosis resistance by an
unknown mechanism (Carlsson et al., 2003). Note
that other S. pyogenes surface structures, not
shown here, may also affect complement deposition
and phagocytosis resistance.
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Induction of inflammation and apoptosis
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• Inflammation, endothelial damage, multi-organ
  failure and shock
• M protein and SPE superantigen

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The Journal of Immunology, 2006, 177 12211228.
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Autoimmunity post-infectious sequelae
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Considerable insight has been gained into the
etiopathogenesis of poststreptococcal
glomerulonephritis since the landmark theoretical
construct of Clemens von Pirquet postulated that
disease-causing immune complexes were responsible
for the nephritis that followed scarlet fever.
Over the years, molecular mimicry between
streptococcal products and renal components,
autoimmune reactivity and several streptococcal
antigens have been extensively studied. Recent
investigations assign a critical role to both in
situ formation and deposition of circulating
immune complexes that would trigger a variety of
effector mechanisms. Glomerular plasmin-binding
activity of streptococcal glyceraldehyde-3-phospha
te-dehydrogenase may play a role in
nephritogenicity and streptococcal pyrogenic
exotoxin B and its zymogen precursor may be the
long-sought nephritogenic antigen.
Kidney International (2007) 71, 10941104.
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Streptococcal pyrogenic exotoxin B is an
extracellular cysteine protease. Only
nephritis-associated strains of group A
streptococci secrete this protease and this may
be involved in the pathogenesis of
post-streptococcal glomerulonephritis. Mice were
actively immunized with a recombinant protease
inactive exotoxin B mutant or passively immunized
with exotoxin B antibody.Characteristics of
glomerulonephritis were measured using histology,
immunoglobulin deposition, complement activation,
cell infiltration, and proteinuria. None of the
mice given bovine serum albumin or exotoxin A as
controls showed any marked changes.
Immunoglobulin deposition, complement activation,
and leukocyte infiltration occurred only in the
glomeruli of exotoxin B-hyperimmunized mice. One
particular anti-exotoxin B monoclonal antibody,
10G, was cross-reactive with kidney endothelial
cells and it caused kidney injury and proteinuria
when infused into mice. This cross-reactivity may
be involved in the pathogenesis of
glomerulonephritis following group A
streptococcal infection.
Kidney International (2007) 72, 716724
doi10.1038/sj.ki.5002407
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Autophagy
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Vaccinology
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Vaccine development has emerged as a compelling
example of the benefits of genomics. In the last
five years, the traditional, linear process of
testing antigens one at a time has been
revolutionized by genome-scale, parallel
strategies for discovering candidate antigens
an approach commonly referred to as reverse
vaccinology.
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We describe a proteomic approach for identifying
bacterial surface-exposed proteins quickly and
reliably for their use as vaccine candidates.
Whole cells are treated with proteases to
selectively digest protruding proteins that are
subsequently identified by mass spectrometry
analysis of the released peptides. When applied
to the sequenced 1_SF370 group A Streptococcus
strain, 68 PSORT-predicted surface-associated
proteins were identified, including most of the
protective antigens described in the literature.
The number of surface-exposed proteins varied
from strain to strain, most likely as a
consequence of different capsule content. The
surface-exposed proteins of the highly virulent
23_DSM2071 strain included 17 proteins, 15 in
common with M1_SF370. When 14 of the 17 proteins
were expressed in E. coli and tested in the mouse
for their capacity to confer protection against a
lethal dose of M23_DSM2071, one new protective
antigen (Spy0416) was identified. This strategy
overcomes the difficulties so far encountered in
surface protein characterization and has great
potential in vaccine discovery.
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