Transcript Slide 1
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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