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Rebecca Walsh
Smith College
BIO 360
Spring 2005
Outline
History of S.pyogenes
 Epidemiology
 Biology
 Vaccine Development
 Conclusions

Title Slide image from:
http://www.geo.de/GEO/fotografie/portfolio_des_monats/2001_10_portfolio_meckes/page13.html?linkref=geode_pager
History

5th century BC – Hippocrates

1874 – Billroth

1884 – Pasteur

Late 19th century – Rosenbach
http://www.mja.com.au/public/issues/177_11_021202/dec10354_fm.html

1919 – Brown

1930’s – Lancefield

1980’s/90’s
http://medicine.ucsd.edu/nizetlab/
streptococcipage/streptococci.html
Outline
History of S.pyogenes
 Epidemiology

 Transmission
 Frequency
 Confirmation
Tests
 Treatment
Biology
 Vaccine Development
 Conclusions

Transmission

Initially colonizes skin and
pharynx

Person-to-person spread

Strains that cause skin
infections are spread via skin
contact
 Strains that cause respiratory
infections are spread via
respiratory droplets

Less common is food or
waterborne

The immunucompromised are
especially susceptible
http://www.cellsalive.net/photos/
Frequency

In the US:

Study from 1995-1999 showed
that invasive GAS infections
occurred in 3.6/100,000 people
annually
 Upper respiratory tract infections
most common in northern regions
 Skin infections most frequent
during summer

Internationally:

Skin infections most common in
the tropics
http://textbookofbacteriology.net/normalflora.html
Tests to Confirm Infection

Rapid Ag detection

Culture
 Beta-hemolysis
 PYRase
Beta-Hemolysis
 Bacitracin
Bacitracin
http://www.med.sc.edu:85/fox/streptococci.htm
http://www.austin.cc.tx.us/microbugz/44a_p.html
Treatment

Penicillin


Clindamycin


Inhibits RNA-dependent
protein synthesis
Vancomycin


Interferes with the
synthesis of a peptide in
the bacterial cell wall
For people allergic to
penicillin
Vaccines
“Staphylococcus aureus growth is inhibited
in the area surrounding the invading
penicillin-secreting Penicillium mold colony.”
http://www.accessexcellence.org/AE/AEC/CC/s5.html
Outline
History of S.pyogenes
 Epidemiology
 Biology

 Basic
Information
 Diseases
 Genome
 Virulence Factors
Vaccine Development
 Conclusions

Biology Basics

Gram-positive bacterium

Occur in pairs or short
chains

Cells are 0.6-1.0 μm in
diameter

Further subdivided by
serotypes
http://textbookofbacteriology.net/BSRP.html
Diseases
Pathogenesis of S.pyogenes Infections
http://www.textbookofbacteriology.net/streptococcus.html
Diseases Cont’d
Image taken from:
Batzloff, et al.
Strep Throat

S.pyogenes is leading cause
of uncomplicated bacterial
pharyngitis and tonsillitis

Common in winter and early
spring in children over age 3

Typical symptoms:


Pus in throat
Reddened and inflamed tonsils
and uvula
 Tiny, reddish-brown spots at back
of throat
 Swollen lymph nodes and tongue

Treatment is best 48 hours
after symptom onset
http://www.lib.uiowa.edu/hardin/md/strepthroat.html
Acute Rheumatic Fever

Inflammatory disease
mediated by autoimmune
mechanisms activated by GAS
infection

Typically follows pharyngitis

Symptoms include migratory
arthritis, chorea, and carditis

20 million new cases annually
Chest radiograph
of an 8 year-old
patient with acute
carditis before
(←) treatment,
and after 4 weeks
of treatment (↓)
http://www.health.gov.mt/impaedcard/issue/issue11/1231/1231.htm
S.pyogenes Necrotizing Fasciitis

“Flesh-eating bacteria”

600 cases annually in US

Rapidly progressive
http://www.aic.cuhk.edu.hk/web8/toc.htm

Any part of body can be infected

Common in abdomen, perineum, and
extremities

Patients present with red skin,
lesions

Untreated patients will die within 4
days
http://catalog.nucleusinc.com/gener
ateexhibit.php?ID=11447&ExhibitKe
ywordsRaw=&TL=16353&A=2
S.pyogenes Genome

Approximately 1,900,000
base pairs

Has over 40 virulenceassociated genes

Numerous genes
involved in molecular
mimicry
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=11296296
Virulence Factors
Known or Postulated GAS
Virulence Factors in Humans

Involved in:
 Antiphagocytosis
 Adherence
 Internalization
 Invasion/spread
through host tissues
 Systemic toxicity
Image adapted from:
Bisno, et al.
Virulence Factors Cont’d
Image taken from:
http://www.textbookofbacteriology.net/streptococcus.html
Mitchell
Host Response

S.pyogenes is usually an
exogenous secondary
invader

Skin is first line of
defense

Host phagocytic system
is second line of defense

Protective immunity is
third line of defense
Phagocyte Engulfing GAS Chain
http://www.cellsalive.com/strep.htm
Extracellular Products

Act to kill host cells and
provoke inflammation

Invasins
Invasin

Streptococcal pyrogenic
exotoxins
Superantigen
http://www.cco.caltech.edu/~astrid/invasin.html
http://www.mgc.ac.cn/VFs/Figures/Streptococcus/superantigen.png
Hyaluronic Acid Capsule

Non-antigenic

Adhesin

Prevents opsonized
phagocytosis

Amount of encapsulation
varies between GAS
strains

“A Bacterial Capsule Preventing
Receptors on Phagocytes from
Binding to Bacterial Cell Wall”
Highly encapsulated strains
with lots of M protein are
associated with invasive
GAS diseases
http://www.cat.cc.md.us/courses/bio141/lecguide/unit1/bacpath/capc3b.html
M Protein

Major virulence factor

Composed of 3 regions:



Hypervariable (N-terminus)
Variable (A- and B-repeats)
Conserved (C-repeats)

Antigenic differences in the
hypervariable region constitute
the basis for the Lancefield
serological classification of
GAS

Over 120 types

Antibodies against one type
confer no protection against
others
Image taken from:
Bisno, et al.
Complement Pathway
Image taken from:
Mitchell
M Protein Cont’d

Involved in colonization and
resistance to phagocytosis

Mediates antiphagocytic effect by
inhibiting activation of alternate
complement pathway

Confers resistance to
phagocytosis because it acts as
an adhesin

Shares sequence homology with
mammalian fibrillar proteins,
providing a structural basis for
induction of autoimmunity
following GAS infection
http://www.rockefeller.edu/vaf/m.htm
Outline
History of S.pyogenes
 Epidemiology
 Biology
 Vaccine Development

 Current
Situation
 Potential Vaccines

Conclusions
Vaccine Development

Other Streptococci?

Difficulties in targeting
the M protein
 Variability
 Cross-Reactivity
http://www.montana.edu/ww
wwami/523/Reading11.htm
Multivalent Vaccines

Study by Dey, et al.

Surveyed GAS emm
types from India

Results showed high
number of types with no
predominant strain


Need for multivalent
vaccines
Geographic bias in
distribution?
Image taken from:
Dey, et al.
Potential Vaccines

Recombinant
 Serotypic
determinant
approach

StreptavaxTM
 Conserved
region
approach

Synthetic peptide
http://www.auburnschl.edu/OtherInfo/immunizations.html
Conclusions

Causes numerous
diseases

Increasing bacterial
resistance to treatment

Many virulence factors
provide options for
vaccine development

Currently, the M protein is
our best vaccine target
option, and StreptavaxTM is
our best hope for a vaccine
http://www.microbiology.emory.edu/scott/index_main.htm
Thank you!

In appreciation for
their contributions:
 Dr.
Christine WhiteZiegler
 Reviewers Jill Falk
and Barbara JenningsSpring
 Individuals whose
websites provided the
images for this
presentation
http://www.smbs.buffalo.edu/wcmpi/faculty/stinson.html
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