Streptococc

us

pyogenes

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

1919 – Brown

1930’s – Lancefield

1980’s/90’s

http://www.mja.com.au/public/issues/177_11_021202/dec10354_fm.html

http://medicine.ucsd.edu/nizetlab/streptococcipage/streptococci.html

Outline

History of S.pyogenes Epidemiology

TransmissionFrequencyConfirmation TestsTreatment

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 Bacitracin

http://www.med.sc.edu:85/fox/streptococci.htm http://www.austin.cc.tx.us/microbugz/44a_p.html

Beta-HemolysisBacitracin

Treatment

Penicillin Interferes with the

synthesis of a peptide in the bacterial cell wall

Clindamycin Inhibits RNA-dependent

protein synthesis

Vancomycin For people allergic to

penicillin

Vaccineshttp://www.accessexcellence.org/AE/AEC/CC/s5.html

“Staphylococcus aureus growth is inhibited in the area surrounding the invading penicillin-secreting Penicillium mold colony.”

Outline

History of S.pyogenes Epidemiology Biology

Basic InformationDiseasesGenomeVirulence 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

http://www.textbookofbacteriology.net/streptococcus.html

Pathogenesis of S.pyogenes Infections

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

http://www.health.gov.mt/impaedcard/issue/issue11/1231/1231.htm

Chest radiograph of an 8 year-old patient with acute carditis before (←) treatment, and after 4 weeks of treatment (↓)

S.pyogenes Necrotizing Fasciitis

“Flesh-eating bacteria”

600 cases annually in US

Rapidly progressive

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/

generateexhibit.php?ID=11447&ExhibitKeywordsRaw=&TL=16353&A=2

http://www.aic.cuhk.edu.hk/web8/toc.htm

S.pyogenes Genome

Approximately 1,900,000 base pairs

Has over 40 virulence-associated genes

Numerous genes involved in molecular mimicry

http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=11296296

Virulence Factors

Involved in: Antiphagocytosis Adherence Internalization Invasion/spread

through host tissues Systemic toxicity

Known or Postulated GAS Virulence Factors in Humans

Image adapted from:

Bisno, et al.

Virulence Factors Cont’d

◄

►

http://www.textbookofbacteriology.net/streptococcus.html

Image taken from:

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

http://www.cellsalive.com/strep.htm

Phagocyte Engulfing GAS Chain

Extracellular Products

Act to kill host cells and provoke inflammation

Invasins

Streptococcal pyrogenic exotoxins

http://www.cco.caltech.edu/~astrid/invasin.html

Invasin

Superantigen

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 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

“A Bacterial Capsule Preventing Receptors on Phagocytes from Binding to Bacterial Cell Wall”

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 SituationPotential Vaccines

Conclusions

Vaccine Development

Other Streptococci? Difficulties in targeting the M protein Variability Cross-Reactivity

http://www.montana.edu/wwwwami/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!

http://www.smbs.buffalo.edu/wcmpi/faculty/stinson.html

In appreciation for their contributions: Dr. Christine White-

Ziegler Reviewers Jill Falk and

Barbara Jennings-Spring

Individuals whose websites provided the images for this presentation

ReferencesAmerican Society of Clinical Pathologists.

http://www.api-pt.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/groupastreptococcal_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/strpyoge.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’dMedina, 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/202590.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/bacteria/gram-positive/streptococcus/streptococcus.htm?name=Streptococcaceae. 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.