Download Group B Strep

Group B Streptococcus:
Not just a mother’s problem
Group B Streptococcus induces trophoblast death.
Kaplan, Amber; et al. Microbial Pathogenesis.
Sept. 2008; 45(3): 231-235.
By: Cassie Saikin, Microbial Pathogenesis
Group B Streptococcus (GBS)
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Streptococcus agalactiae
Gram positive
Encapsulated
Commensal in vagina, GI tract
Strong adherence to epithelial
cells
Leading cause of neonatal
infection
◦ pneumonia, prenatal
delivery, septicemia, and
meningitis
Neonatal Infection
EARLY ONSET
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Ascending infection
6-8 hours to 7 days after birth
Characterized by:
◦ Pneumonia, respiratory failure,
septicemia
LATE ONSET
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Up to 7 months after birth
Characterized by:
◦ Septicemia, neonatant
meningitis
• GBS virulence:
• Adhesion  penetration immune evasion inflammation
• Penetration of host cell barriers is indication of pathogenicity
GBS Epithelial Adhesion
Serotype III (capsule characteristic) – most capable of
adhering to neonate epithelial cells
 Neonates colonized with GBS – increased expression of
attachment receptors
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◦ Lipoteichoic Acid (LTA) receptors
◦ Interact with extracellular matrix proteins – fibronectin, fibrinogen,
laminin
Hypothesis
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GBS induces apoptosis of trophoblast cells by βhemolysis, conducted by the bacterial protein βhemolysin/cytolysin.
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Trophoblast death is responsible for neonatal
infection.
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β-hemolysin/cytolysin is responsible for GBS
toxicity.
β-hemolysin/cytolysin
Pore-forming toxin – punctures holes in epithelial surfaces
◦ Weakens cell-barrier integrity (within placenta –
trophoblasts) – allow for invasion
 Contributes to GBS pathogenicity/toxicity:
◦ Direct tissue damage
◦ Triggering apoptosis
◦ Promotion of intracellular invasion
◦ Immune evasion
◦ Activation of host inflammatory response
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β-hemolysis – cytolytic damage and trophoblast death
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Leads to bacterial destruction and invasion of
trophoblasts (placental epithelial tissue)
Proving the hypothesis
◦ Exposed human JEG3 trophoblast cells and primary placental
trophoblasts and fibroblasts to varying levels of purified βhemolysin/cytolysin or GBS isolates with varying degrees of
hemolytic activity
 NCTC10/84 – high hemolytic activity (wildtype)
 COH1 strain – low hemolytic activity
 Mutant NCTC10/84 – no hemolytic activity (null)
◦ Measured cell death by colorometric lactate dehydrogenase
(LDH) assay – measured the supernatant levels of active LDH
◦ Experiments performed in triplicate
Results of study
Exposure to high levels of β-hemolysin/cytolysin from wildtype strain (NCTC10/84) induces trophoblast death in
comparison with low levels (COH1 strain) and mutant
strain (mutant NCTC10/84)
 Cell death is dose-dependent in relation to levels of βhemolysin/cytolysin
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◦ Higher levels results in increased death
Figure 5. Exposure to varying βhemolysin/cytolysin levels
Chorioamnionitis
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Destruction of placental cells by GBS leads to amniotic fluid
infections and chorioamnionitis (inflammation of placental
amniotic membranes) – raises risk for neonatal infection
Chorioamnion – bilayer of cells
◦ Monolayer of chorion epithelial cells – maternal side of placenta
◦ Monolayer of amnion epithelial cells – embryonic side of placenta
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GBS can bind to both chorion cells and amnion cells, but only
invades and survive within chorion cells.
◦ Weakens the placental barrier, invade and transcytose through the
bilayer of epithelial cells into the placenta
◦ Invasion of the placenta gives GBS access to the fetus in the
amniotic cavity
Immune Evasion and
Host Inflammatory Response
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Phagocytic evasion
◦ β-hemolysin/cytolysin – cytolytic damage and apoptosis of
phagocytes
◦ GBS can survive within immature phagocytes – evade oxidative
stress
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CiaR response
◦ AMP-resistance
◦ Survive in epithelial cells and blood stream
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Activation of host-inflammatory responses – sepsis, multiorgan
failure
◦ Release of inflammatory mediators
◦ Amount of inflammatory mediators proportional to severity of
placental infection
Neonatal Meningitis
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β-hemolysin/cytolysin
◦ Direct cytolytic damage to brain microvascular endothelial cells
(BMEC), which allows GBC to breach the blood brain barrier
(BBB)
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GBS is able to infect the lungs, where βhemolysin/cytolysin causes destruction of the lung
epithelia and weakening the tensile strength of the
epithelial barrier = easy access to blood stream
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Survival in blood stream – travel to brain and transcytose
through BBB
◦ β-hemolysin/cytolysin destroys BMEC
◦ GBS takes control of CNS
For the Future
Research into the complications of bacterial prophylaxis by
antibiotics
 Vaccine development against neonate GBS infection.
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◦ Vaccines targeted against GBS serotype proteins of the streptococcal
capsule are currently in phase III clinical trials.
◦ Investigation into currently-known bacterial factors as well as potential
virulence factors could lead to new insights into a vaccine to protect
neonates from this frightfully dangerous organism.
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Genomic research has discovered other protein factors that
contribute to GBS virulence, including LTA, serine protease,
fibrinogen receptor, and C5a peptidase. Further research into new
virulence factors such as transcriptional factors, especially those that
are homologous to other Streptococcus strains, could aid in the
discovery of targets for prophylaxis and prevention as well as a
common ancestor of the streptococcal species.
References
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[1] Berner, R. Significance, management, and prevention of Streptococcus agalactiae infection
during the perinatal period. Expert Rev Anti Infect Ther. 2004 Jun;2(3):427-37.
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[2] De Paepe, Monique E, et al. The Histological Fetoplacental Inflammatory Response in Fatal
Perinatal Group B-Streptococcus Infection. Journal of Perinatology. 2004; 24:441-445.
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[3] Doran, Kelly S., Victor Nizet. Molecular pathogenesis of neonatal group B streptococcal
infection: no longer in its infancy. Molecular Microbiology. 2004; 54(1):23-31.
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[4] Kaplan, Amber, et al. Group B streptococcus induces trophoblast death. Microbial
Pathogenesis. 2008; 45(3): 231-235.
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[5] Quach, Darin, et al. The CiaR Response Regulator in Group B Streptococcus Promotes
Intracellular Survival and Resistance to Innate Immune Defences. Journal of Bacteriology. 2009;
191(7):2023-2032.
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[6] Teti, Giuseppe, et al. Adherence of Group B Steptococci to Adult and Neonatal Epithelial Cells
Mediated by Lipoteichoic Acid. Infection and Immunity. 1987; 55(12):3057-3064.
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[7] Winram, Scott B, et al. Characterization of Croup B Streptococcal Invasion of Hman Chorion
and Amnion Epithelial Cells In Vitro. Infection and Immunity. 1998; 66(10):4932-4941.