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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
Introduction
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
Pathogenesis and host responses
Host-streptococcus interactions
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.
Graham et al. Group A Streptococcus transcriptome dynamics
during growth in human blood reveals bacterial adaptive and
survival strategies. Am J Pathol 2005, 166:456-465.
Shelburne et al. Growth characteristics of and virulence factor
production by group A Streptococcus during cultivation in
human saliva. Infect Immun 2005, 73:4723-4731.
Graham et al. Analysis of the transcriptome of group A
Streptococcus in mouse soft tissue infection. Am J Pathol 2006,
169:927-942.
Innate immune responses
J. Allergy Clin. Immunol., 2007;120:13-22
Inhibition of PMN recruitment and phagocytosis (I)
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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
Inhibition of PMN recruitment and phagocytosis (II)
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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 IgGmediated opsonophagocytosis
Hyaluronic acid capsule:
Act as a physical barrier to prohibit interaction of PMN with opsonins on
bacterial surface
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.
Induction of inflammation and apoptosis
Inflammation, endothelial damage, multi-organ failure and shock
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M protein and SPE superantigen
The Journal of Immunology, 2006, 177: 1221–1228.
Autoimmunity: post-infectious sequelae
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-phosphate-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, 1094–1104.
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, 716–724; doi:10.1038/sj.ki.5002407;
Autophagy
Vaccinology
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”.
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.