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
References
American Society of Clinical Pathologists. http://www.apipt.com/pdfs/2001Bmicro.pdf. 2001.
Batzloff MR, Sriprakash KS, Good MF. Vaccine
development for group A Streptococcus infections
and associated diseases. Current Drug Targets
2004; 5(1): 57-69.
Bisno AL, Brito MO, Collins CM. Molecular basis of group
A streptococcal virulence. The Lancet Infectious
Diseases 2003; 3: 191-200.
Centers for Disease Control and Prevention. Group A
streptococcal (GAS) disease.
http://www.cdc.gov/ncidod/dbmd/diseaseinfo/groupa
streptococcal_g.htm. 2003.
Columbia Encyclopedia, Sixth Edition. Bacitracin.
http://www.encyclopedia.com/htl/b1/bacitrac.asp.
2005.
Dey N, McMillan DJ, Yarwood PJ, et al. High diversity of
group A streptococcal emm types in an Indian
community: the need to tailor multivalent vaccines.
Clinical Infectious Diseases 2005; 40: 46-51.
Duckworth D. Streptococcus pyogenes.
http://medinfo.ufl.edu/year2/mmid/bms5300/bugs/str
pyoge.html. 1999.
Farlander. Streptococcus pyogenes – killer flesh-eating
bacteria. http://www.bbc.co.uk/dna/h2g2/A907481.
2003.
Ferretti JJ, McShan WM, Ajdic D, et al. Complete
gemone sequence of an M1 strain of Streptococcus
pyogenes. Proceedings of the National Academy of
Sciences 2001; 98(8): 4658-4663.
Geetha D. Glomerulonephritis, poststreptococcal.
http://www.emedicine.com/med/topic889.htm. 2004.
Haorui Pharma-Chem Inc. Vancomycin HCl.
http://www.haoruiusa.com/API/Vancomycin.htm.
2005.
Horváth A, Olive C, Karpati L, et al. Toward the
development of a synthetic group A streptococcal
vaccine of high purity and broad protective
coverage. J. Med. Chem. 2004; 47(16): 4100-4104.
Janeway CA Jr, Travers P, Walport M, Shlomchik MJ.
Immunobiology: the immune system in health and
disease. Sixth Ed. New York: Garland Science
Publishing. 2005.
Kessenich CR, Bahl A. Necrotizing fasciitis:
understanding the deadly results of the uncommon
‘flesh-eating bacteria.’ AJN 2004; 104(9): 51-55.
Kotloff KL, Dale JB. Progress in group A streptococcal
vaccine development. The Pediatric Infectious
Disease Journal 2004; 23(8): 765-766.
McMillan DJ, Davies MR, Browning CL, Good MF,
Sriprakash KS. Prospecting for new group A
streptococcal vaccine candidates. Indian J Med Res
2004; 119(Suppl): 121-125.
Meador RJ. Acute rheumatic fever.
http://www.emedicine.com/med/topic2922.htm.
2004.
Medina E, Chhatwal GS. The potential for vaccine
development against rheumatic fever. Indian Heart
Journal 2002; 54(1): 93-98.
References Cont’d
Medina, E, Goldmann O, Toppel AW, Chhatwal GS.
Survival of Streptococcus pyogenes within host
phagocytic cells: a pathogenic mechanism for
persistence and systemic invasion. JID 2003; 187:
597-603.
Mitchell, TJ. The pathogenesis of streptococcal
infections: from tooth decay to meningitis. Nature
Reviews 2003; 1: 219-230.
Molinari, G, Rohde M, Guzmán CA, Chhatwal GS. Two
distinct pathways for the invasion of Streptococcus
pyogenes in non-phagocytic cells. Cellular
Microbiology 2000; 2(2): 145-154.
Nakagawa I, Amano A, Mizushima N, et al. Autophagy
defends cells against invading group A
Streptococcus. Science 2004; 306: 1037-1040.
National Institutes of Health. Vancomycin (systemic).
http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/2
02590.html. 1999.
Olive C, Batzloff MR, Toth I. Lipid core peptide
technology and group A streptococcal vaccine
delivery. Expert Rev. Vaccines 2004; 3(1): 43-58.
Pérez-Caballero D, García-Laorden I, Cortés G, et al.
Interaction between complement regulators and
Streptococcus pyogenes: binding of C4b-binding
protein and factor H/factor H-like protein 1 to M18
strains involves two different cell surface molecules.
The Journal of Immunology 2004; 173: 6899-6904.
Schleiss MR. Streptococcal infection, group A.
http://www.emedicine.com/ped/topic2702.htm.
2005.
Schwartz RA. Necrotizing fasciitis.
http://www.emedicine.com/derm/topic743.htm.
2005.
Sharma S. Streptococcus group A infections.
http://www.emedicine.com/med/topic2184.htm.
2004.
Stevens DL, Madaras-Kelly KJ, Richards DM. In vitro
antimicrobial effects of various combinations of
penicillin and clindamycin against four strains of
Streptococcus pyogenes. Antimicrobial Agents and
Chemotherapy 1998; 42(5): 1266-1268.
Stulberg M, Smith CM, Scogin S, Sacks H.
Streptococcus.
http://biology.kenyon.edu/Microbial_Biorealm/bacteri
a/grampositive/streptococcus/streptococcus.htm?name=St
reptococcaceae. 2002.
Todar, K. Streptococcus pyogenes.
http://textbookofbacteriology.net/streptococcus.html.
2002.
Wizemann TM, Adamou JE, Langermann S. Adhesins as
targets for vaccine development. Emerging
Infectious Diseases 1999; 5(3): 395-403.