Date post: | 24-Dec-2015 |
Category: |
Documents |
Upload: | thomasine-bates |
View: | 216 times |
Download: | 0 times |
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.