9 Group B Streptococcus Meningitis
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9 Group B Streptococcus Meningitis
Victor Nizet1 and Kelly S. Doran1,2*
1University of California at San Diego, California, USA; 2San Diego State University,
San Diego, USA
9.1 Introduction infections are traditionally divided among
two forms: early-onset disease (EoD) and
Streptococcus agalactiae (Group B Streptococcus, late-onset disease (LoD). Early-onset in-
GBS) is a Gram-positive encapsulated fections are described to occur through the
bacterium possessing an array of virulence first 7 days of life, but in fact have a median
factors that render it capable of producing onset of only 6–8 h of life, presenting acutely
serious disease in susceptible hosts, in with pneumonia and respiratory failure
particular the human newborn (Maisey et al., complicated by bloodstream infection and
2008a). Notably, GBS is the leading cause of septicaemia. GBS EoD cases result from
meningitis in the neonatal period (Brouwer et ascending infection of the bacterium through
al., 2010; Thigpen et al., 2011). Although the placental membranes to initiate infection
advances in intensive care management and in utero, or, alternatively, by aspiration of
antibiotic therapy have changed GBS infected vaginal fluids during the birth
meningitis from a uniformly fatal disease to a process. Premature, low-birth-weight infants
frequently curable one, the overall outcome are at increased risk of developing early-
remains unfavourable. Morbidity is high; onset infection, with GBS placental infection
25–50% of surviving infants suffer neuro- itself often the critical factor triggering
logical sequelae of varying severity, including premature labour. In contrast, GBS LoD
cerebral palsy, mental retardation, blindness, occurs in infants up to 7 months of age, with
deafness or seizures. more indolent symptom progression related
The pathogenesis of neonatal GBS to bacteraemia, absence of lung involvement
infection begins with the asymptomatic and a high incidence (~50%) of meningitis
colonization of the female genital tract. (Baker and Edwards, 2001). Universal
Approximately 20–30% of healthy women screening of pregnant women at 35–37 weeks
are colonized with GBS on their vaginal or gestation and intrapartum antibiotic
rectal mucosa, and 50–70% of infants born to prophylaxis has resulted in a decline in early-
these women will themselves become onset GBS invasive disease in the USA (Phares
colonized with the bacterium (Baker and et al., 2008; Van Dyke et al., 2009). However,
Edwards, 2001). For the purposes of this treatment has not eliminated the
epidemiological classification, neonatal GBS incidence of GBS meningitis, and concern has
*kdoran@mail.sdsu.edu
© CAB International 2013. Meningitis: Cellular and Molecular Basis
118 (ed. M. Christodoulides)Group B Streptococcus Meningitis 119
been raised about concurrent increases in fluid barrier (BCSFB). For the purposes of this
non-GBS early-onset bacterial infections, review, the BBB and BCSFB are inter-
especially in pre-term infants as a result of changeable concepts with respect to vessel
increased antibiotic use (Stoll et al., 2002a,b). endothelial cell penetration by GBS.
Furthermore, the occurrence of GBS Disruption of BBB integrity is a hallmark
meningitis in older children or adults is more event in the pathophysiology of bacterial
commonly appreciated, with an approximate meningitis. This disruption may be due to the
4% increase in total number of cases reported combined effect of bacterial entry and
between 1997 and 2007 in the USA (Thigpen penetration of brain microvascular endo-
et al., 2011). No vaccination strategies are thelial cells (BMECs), direct cellular injury by
currently in place to prevent GBS infections, bacterial cytotoxins, and/or activation of host
but if ultimately achieved they would be inflammatory pathways that compromise
anticipated to reduce the number of BMEC barrier function. It is apparent that the
meningitis cases (Thigpen et al., 2011). Here host immune response is not only incapable
we review the current understanding of the of controlling infection within the CNS but
pathogenesis of GBS meningitis, highlighting also may be responsible for many adverse
important bacterial virulence factors and host events during bacterial meningitis (Tunkel
interactions that promote disease progression. and Scheld, 1995). A very complex and
integrated series of events involving host
cytokines, chemokines, proteolytic enzymes
9.2 Pathophysiology of GBS and oxidants appears to be responsible for
Meningitis meningitis-induced brain dysfunction. The
development of GBS meningitis progresses
The pathophysiology of GBS meningitis through phases including: (i) bloodstream
varies according to age of onset. In EoD, survival and the development of bacteraemia;
autopsy studies demonstrate little or no (ii) direct GBS invasion and disruption of the
evidence of leptomeningeal inflammation, BBB/BCSFB; and (iii) GBS multiplication in
despite the presence of abundant bacteria, the CSF-containing subarachnoid and ven-
vascular thrombosis and parenchymal tricular spaces, which induces inflammation
haemorrhage (Quirante et al., 1974). By with associated pathophysiological alter-
contrast, infants with LoD usually have dif- ations leading to the development of neural
fuse purulent arachnoiditis with prominent damage. Brain injury results mainly from
involvement of the base of the brain (Berman cerebrovascular involvement leading to
and Banker, 1966). Similar age-related cerebral ischaemia, brain oedema, hydro-
differences in central nervous system (CNS) cephalus and increased ICP.
pathology are evident in the infant rat model
of invasive disease (Ferrieri et al., 1980). These
histopathological differences reflect under- 9.2.1 Bloodstream survival and the
development of the host immunological development of bacteraemia
response in the immediate neonatal period,
with a higher proportion of deaths resulting An association between sustained high-level
from overwhelming septicaemia. Clinical and bacteraemia and the development of GBS
neuropathological studies have documented meningitis has been suggested in humans and
the clear association between bacterial in experimental models of haematogeneous
meningitis and brain oedema formation, meningitis (Ferrieri et al., 1980; Doran et al.,
increased intracranial pressure (ICP), seizure 2002a). This observation implies that GBS
activity, arterial and venous cerebral vascular bloodstream survival is an important
insults, and other neurological sequelae virulence trait to avoid immune clearance by
(Scheld et al., 2002). phagocytic killing by host immune cells, prior
To produce meningitis, blood-borne GBS to CNS penetration. Neonates are particularly
must typically penetrate the blood–brain prone to invasive disease because of their
barrier (BBB) and/or the blood–cerebrospinal quantitative or qualitative deficiencies in120 V. Nizet and K.S. Doran
phagocytic cell function, specific antibody, or 2007). The β-antigen of C protein binds human
the classical and alternative complement IgA antibody (Jerlstrom et al., 1991), and non-
pathways. In addition to these newborn host specific deposition of IgA on the bacterial
susceptibilities, GBS possess a number of surface probably inhibits interactions with
virulence determinants that promote blood- complement. Finally, a cell-surface protease,
stream survival by thwarting key components CspA, targets host fibrinogen, producing
of effective opsonophagocytic killing such as adherent fibrin-like cleavage products that
complement (Fig. 9.1). For example, the coat the bacterial surface and interfere with
surface-anchored GBS β-protein prevents complement-mediated opsonophagocytic
opsonophagocytosis by binding short clearance (Harris et al., 2003).
consensus repeats found in the middle region The profile of GBS gene transcription
of factor H, a host counter-regulator of changes dramatically during growth in
complement (Maruvada et al., 2008), enabling human blood, resulting in an altered cell
the unbound active region to block C3b morphology and increased expression of
deposition on the bacterial cell surface (Jarva complement regulatory proteins (Santi et al.,
et al., 2004). In addition, the cell-surface GBS 2007; Mereghetti et al., 2008). The sialylated
immunogenic bacterial adhesin (BibA) binds GBS capsular polysaccharide (CPS) represents
human C3bp, promoting resistance to one of the most critical factors for limiting the
phagocytic killing and contributing to effectiveness of host complement and
virulence in the mouse model (Santi et al., phagocytic defence. Passage of GBS in animals
Interference with
C3 complement function
Phagocyte lysis
and apoptosis Factor H
C3 Fibrinogen C3bp
β-protein
CspA BibA
H2O2 Fibrin-like
O2– fragments
Antioxidant
defence GBS
C3
pigment
SOD Sialic acid in
polysaccharide
Capsule
β-haemolysin/
cytolysin
Bind/sequester
Charge repulsion PBP1a (pilus subunit PilB)
(Dlt operon)
Antimicrobial peptide
resistance
Fig. 9.1. Mechanisms of GBS immune evasion. GBS express multiple surface-exposed or secreted
factors to evade host immune defences and promote bloodstream survival. The PBP1a and the PilB
subunit of GBS pili contribute to antimicrobial peptide resistance. The Dlt operon is responsible for
increasing incorporation of D-alanine residues in cell-wall teichoic acids, thereby reducing
electronegativity and affinity for cationic antimicrobial peptides. ScpB, the sialic acid capsule, BibA,
-protein and CspA all inhibit host clearance of GBS by interfering with complement components C5a,
C3 and C3bp. Superoxide dismutase (SOD) properties of the orange carotenoid pigment shield GBS
from killing by phagocyte-generated reactive oxygen species. Alternatively, -haemolysin/cytolysin can
boost GBS survival by cytolytic or pro-apoptotic injury to host phagocytes.Group B Streptococcus Meningitis 121
increases capsulation, while serial in vitro carotenoid pigment, a property unique to GBS
passage leads to reduced capsule expression among haemolytic streptococci, associated
(Hakansson et al., 1988), and strains obtained with the cyl operon encoding the
from infants with septicaemia or meningitis β-haemolysin/cytolysin cytotoxin (Spellerberg
have increased encapsulation compared with et al., 2000). The free-radical scavenging
vaginal colonizing strains (Hakansson et al., properties of this carotenoid neutralize
1987). Thus, it appears that GBS capsule hydrogen peroxide, superoxide, hypochlorite
expression is induced during bloodstream and singlet oxygen, and thereby provide a
replication and repressed while on mucosal or shield against several elements of phagocyte
endothelial cell surfaces, a feature common to ROS killing (Liu et al., 2004). Other GBS factors
other meningeal pathogens. Currently, ten that have been linked to survival inside
GBS capsular serotypes have been identified phagocytic cells and/or dendritic cells include
(Ia, Ib, II–IX) based on the different arrange- CPS (Lemire et al., 2012), a pilin protein
ments of four monosaccharides (glucose, (Maisey et al., 2008b) and transcriptional
galactose, N-acetylglucosamine and sialic response regulators CovR (Cumley et al.,
acid) into unique repeating units. Serotype III 2012) and CiaR (Quach et al., 2009), which
GBS strains have accounted for a majority of may coordinate expression of acid and stress
LoD and meningitis (Baker and Edwards, survival genes.
2001; Tazi et al., 2010), but all serotypes contain Another important host defence
a terminal-linked sialic acid bound to mechanism inherent to many immune cells is
galactose in an 2 3 linkage (Cieslewicz the production of small cationic antimicrobial
et al., 2005). The sialic acid moiety provides peptides (AMPs), such as cathelicidins and
antiphagocytic protection by impairing defensins. These peptides are attracted
deposition of opsonically active complement electrostatically to negatively charged micro-
C3 on the bacterial surface. Isogenic GBS bial cell surfaces, followed by their self-
mutants lacking CPS or capsular sialylation assembly to form membrane pores or
are more susceptible to neutrophil killing and otherwise disrupt membrane integrity. GBS
are less virulent in animal models of infection increase their intrinsic resistance to AMPs by
(Campbell et al., 1991; Marques et al., 1992). incorporation of positively charged d-alanine
Furthermore, the conserved GBS terminal residues into their cell wall teichoic acids,
2 3 linked sialic acid capsular component thereby reducing surface electronegative
is identical to a sugar epitope widely displayed charge and affinity for the cationic peptides
on the surface of all mammalian cells. Thus, (Poyart et al., 2001a). A surface-anchored
bacterial surface sialylation may have evolved penicillin-binding protein, PBP1a, enhances
to mimic host ‘self’ antigens, allowing GBS to GBS resistance to cathelicidins and defensins,
avoid immune detection, manipulate thereby reducing GBS susceptibility to killing
phagocyte function and dampen the immune by alveolar macrophages and neutrophils
response to GBS infection (Carlin et al., 2007). and promoting bacterial survival in a neonatal
When GBS are engulfed and contained rat model of GBS infection (Jones et al., 2007).
within the phagosome, a rapid release of toxic Similarly, expression of the pilus backbone
reactive oxygen species (ROS) is produced protein PilB and the action of the two-
through the phagocyte oxidative burst. component regulator CiaR both render GBS
Although GBS do not produce catalase, they more resistant to killing by cathelicidin AMPs
are nevertheless able to resist ROS killing and (Maisey et al., 2008b; Quach et al., 2009).
survive inside macrophage phagolysosomes
(Wilson and Weaver, 1985; Cornacchione et al.,
1998; Teixeira et al., 2001). GBS possess an 9.2.2 GBS invasion of the BBB
endogenous source of the oxygen-metabolite
scavenger glutathione (Wilson and Weaver, Following bloodstream survival, GBS
1985), and the GBS SodA enzyme can interacts directly with BBB endothelium,
neutralize superoxide anions (Poyart et al., which can result in bacterial invasion of the
2001b). GBS also produce an orange BBB with subsequent infection of the CNS.122 V. Nizet and K.S. Doran
This process can result from increased Intracellular invasion (transcytosis)
permeability of the BBB and/or the direct
invasion of BMECs by the pathogen. GBS enter or ‘invade’ brain endothelium
Microbial interaction with the BBB may apically and exit the cell on the basolateral
involve crossing the brain endothelium by side, thereby crossing the BBB transcellularly
direct intracellular invasion and vacuole (Nizet et al., 1997; Lembo et al., 2010). Electron
transit (transcytosis), by passage through the microscopy has demonstrated the presence of
intercellular junctional spaces (paracytosis) the meningeal pathogen in membrane-bound
or by transport inside another host cell vacuoles within HBMECs (Nizet et al., 1997),
(phagocyte-facilitated invasion). With the suggesting the involvement of endocytic
availability of in vitro tissue culture models of pathways as well as avoidance of lysosomal
human (H)BMECs (Stins et al., 1994; Nizet et fusion for BBB traversal. Further HBMEC
al., 1997) and animal models of GBS infection invasion can be blocked by inhibition of actin
(Doran et al., 2003; Tazi et al., 2010), significant polymerization, suggesting that GBS trigger
progress has been made in identifying and rearrangement of the host cytoskeleton and
characterizing the molecular determinants induce their own uptake (Nizet et al., 1997).
that promote GBS–BBB interaction (Fig. 9.2). This process may be accomplished, at least in
Neutrophil
recruitment
Chemokines GBS factors that promote cellular invasion:
(IL-8, CXCL1, CXCL2) ACP, pili, GAPDH, FbsB,
IagA β-haemolysin/cytolysin, LTA, Srr proteins
FbsA/B PilA Srr1
HvgA Alpha C
Fibrinogen, collagen protein
ICAM 1 LTA
Extracellular
Glycosaminoglycan
matrix
Cell damage Paracellular Cytoskeletal
β-haemolysin/
uncovers novel translocation modulation
receptors (mechanism uncertain)
cytolysin
ZO-1 X X
FAK GDP
cPLA2α
Rho/Rac
PI3K Paxillin Rho/Rac
Pili Lmb GTP
PilA
Collagen, laminin
Basal Cellular adherence Cellular invasion
Fig. 9.2. Mechanisms of GBS penetration of the BBB. Surface-expressed proteins FbsA/B, Srr1, PilA,
HvgA, lipoteichoic acid (LTA) and alpha C protein (ACP) mediate GBS binding to host cells and
extracellular matrix (ECM) components, such as fibrinogen and collagen. Secreted -haemolysin/
cytolysin promotes GBS invasion, possibly by breaking down host barriers to reveal novel receptors on
the basement membrane, such as laminin and collagen, as well as promoting neutrophil influx that
contributes to barrier disruption. GBS also use glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to
activate host plasminogen and degrade the ECM. Intracellular GBS invasion is enhanced by bacterial-
dependent cytoskeletal rearrangements triggered by host PI3K/AKT- and FAK-signalling pathways and
the Rho family of GTPases. Alternatively, GBS can also disrupt tight junction complexes to cross the
barrier by a paracellular route. Several GBS adhesins, including FbsB, pili, LTA and ACP, also contribute
to cellular invasion.Group B Streptococcus Meningitis 123
part, by tyrosine phosphorylation of focal (TLR) 2, the data strongly suggest that the
adhesion kinase (FAK), which occurs upon attenuated phenotype of the ∆iagA mutant is
GBS infection. Phosphorylation of FAK not dependent on TLR2 (Doran et al., 2005).
induces its association with PI3K and paxillin, The evidence that the LTA surface polymer
an actin filament adaptor protein (Shin et al., mediates unique host cell interactions is
2006), and is required for efficient invasion of consistent with early epidemiological studies.
HBMECs by GBS. GBS-infected HBMECs Clinical isolates of GBS from infants with
also exhibit increased levels of activated Rho EoD or LoD possess higher quantities of cell-
family members RhoA and Rac1. Rho family associated LTA than strains isolated from
GTPase inhibitors and dominant-negative mucosal surfaces of asymptomatically
expression of RhoA and Rac1 are effective in colonized infants (Nealon and Mattingly,
blocking GBS invasion (Shin and Kim, 2006). 1983). Furthermore, longer LTA polymer
To elucidate the GBS determinants length is characteristic of isolates from
involved in the pathogenesis of meningitis, carriers with invasive GBS disease compared
many groups have focused on the with asymptomatic carriers. LTA is common
characterization of GBS isolates responsible to all GBS sero- and sequence types, but it
for CNS disease. Clinical isolates of serotype remains to be determined if ST-17 clones
III GBS, which are over-represented in LoD, contain longer or structurally distinct LTA
appear to belong to two distinct evolutionary polymers, which may account for their
clusters (Musser et al., 1989), which have now increased virulence.
been shown through multilocus sequence More recently, the availability of GBS
typing to represent a limited number of clonal genome sequences has enabled the
complexes (Jones et al., 2003). Of these clones, identification of genes restricted to the ST-17
sequence type (ST)-17 is strongly associated lineage (Tettelin et al., 2005; Brochet et al.,
with neonatal meningitis and has been 2006). Mosaic variants were identified at a
designated as the hypervirulent clone (Lamy single genomic locus encoding a cell wall-
et al., 2006). Screening of a GBS ST-17 mutant anchored protein, with two main variants
library revealed a unique requirement for the displaying 38% overall amino acid identity,
novel ‘invasion associated gene’, iagA, in BBB namely BibA (Santi et al., 2007), and a second
penetration by GBS (Doran et al., 2005). gene to be strictly specific to the ST-17 clone
Decreased invasion of HBMECs by the GBS (Lamy et al., 2006). This gene, now called
∆iagA mutant in vitro was correlated with a hypervirulent GBS adhesin (HvgA), was
reduced risk for development of meningitis shown to be required for GBS hypervirulence
and markedly diminished lethality in vivo. (Tazi et al., 2010). GBS strains that express
Deletion of iagA did not affect other key steps HvgA are more efficient in gut colonization
in the pathogenesis of GBS meningitis, and in crossing the intestinal–blood barrier
including bloodstream survival, HBMEC and BBB in neonates, including choroid
adherence and intracellular survival. Thus, plexus epithelial cells and brain microvascular
the iagA-encoded phenotype of GBS has a endothelium (Tazi et al., 2010). Furthermore,
specific function in promoting HBMEC heterologous expression of HvgA in non-
uptake of the pathogen. The iagA gene adhesive bacteria conferred the ability to
encodes an enzyme for the biosynthesis of adhere to intestinal barrier and BBB-
diglucosyldiacylglycerol, a membrane glyco- constituting cells.
lipid that functions as an anchor for Serotypes Ia, Ib and V are also commonly
lipoteichoic acid (LTA), indicating that proper isolated from neonates, children and adult
LTA anchoring is important to facilitate patients with meningitis (Phares et al., 2008),
penetration of the BBB by GBS (Doran et al., suggesting that other GBS determinants
2005). The host cell receptor for GBS LTA that prevalent among these serotypes are also
mediates these interactions has yet to be relevant for the pathogenesis of meningitis.
identified. While it is known that LTA is a Proteins targeted for cell surface expression
molecule recognized by Toll-like receptor in GBS are predicted to share a C-terminal124 V. Nizet and K.S. Doran sequence (L/IPXTG) for sortase recognition and promote the establishment of GBS and anchoring to the Gram-positive cell wall. meningitis (Chang et al., 2011). Impaired host Several cell wall-anchored proteins pro- GAG expression diminished GBS penetration moting GBS BBB penetration have been in the CNS in both murine and Drosophila identified and characterized. In a paradigm- models of GBS infection. GBS interactions shifting study, it was discovered that GBS with other ECM components also have been express surface-associated pili (Lauer et al., described. GBS mutants lacking the cell wall- 2005). Among the sequenced GBS genomes, anchored fibrinogen-binding protein FbsA two genetic loci encoding pili have been (Schubert et al., 2004), and the laminin- identified, pilus island (PI)-1 and PI-2, the binding protein Lmb (Spellerberg et al., 1999), second existing in one of two variants (PI-2a have reduced ability to adhere to or invade and PI-2b), and not all genomes contain both HBMECs in vitro (Tenenbaum et al., 2005, loci (Rosini et al., 2006). GBS PI-2a includes 2007). Many GBS strains harbour another the genes encoding PilB, an LP(x)TG-motif- fibrinogen-binding protein, FbsB (Gutekunst containing protein that polymerizes to form a et al., 2004), which is secreted and structurally pilus backbone, and accessory pilus proteins unrelated to FbsA. Interestingly, the PilA and PilC that are incorporated in the expression level of FbsA and FbsB in ST-17 pilus (Dramsi et al., 2006). Both PilA and PilB strains correlated to an increased fibrinogen- promote adherence to and invasion of brain binding capacity that may contribute to the endothelium, respectively (Maisey et al., hypervirulence of this lineage (Al Safadi et 2007), and PilA has been implicated in BBB al., 2011). The GBS genome encodes penetration in vivo using a mouse model of homologues to fibronectin-binding proteins haematogenous GBS meningitis (Banerjee et that contribute to adherence, invasion and al., 2011). Analysis of the PilA protein meningeal inflammation in other strepto- sequence revealed an integrin I-like domain coccal pathogens (Pracht et al., 2005). Whether resembling the A3 domain of human von or not the proteins function in a similar way Willebrand factor, a molecule known to in GBS remains to be determined. interact with collagens. PilA also binds the Fibrinogen is present in the CNS follow- extracellular matrix (ECM) component ing BBB disruption and vascular damage. collagen, and collagen binding enhanced GBS Furthermore, the interaction of fibrinogen attachment as well as uptake into HBMECs in with integrins and non-integrin receptors a dose-dependent manner (Banerjee et al., expressed on cells of the haematopoietic, 2011). The PilA-collagen complex engages immune and nervous systems can induce 2-β1 integrins on brain endothelium to signalling pathways that regulate inflam- promote bacterial attachment and pro- mation and neurodegenerative functions inflammatory chemokine release. As a result, involved in CNS disease. Interestingly, recent increased neutrophil infiltration was studies suggest that adherence to fibrinogen correlated with increased BBB permeability may be a general property of GBS (Dramsi et and higher levels of bacterial CNS penetration al., 2012; Seo et al., 2012) to promote in vivo. This study reveals the deleterious role bloodstream survival and host cell inter- of the neutrophil response to the development actions. An important determinant recently of GBS meningitis, and indicates that the GBS implicated in fibrinogen binding and BBB PilA–BBB interaction is an important interaction are the GBS serine rich repeat molecular event that contributes to disease (Srr) glycoproteins (van Sorge et al., 2009; Seo progression and a detrimental outcome for et al., 2012). Srr proteins have a highly the host. In addition to PilA binding collagen, conserved domain organization, including a other GBS factors interact with various ECM long and specialized signal sequence, two proteins and constituents to promote extensive Srr regions that undergo bacterial–BBB interactions. Recently, the GBS glycosylation, and a typical LP(X)TG cell surface-anchored alpha C protein (APC) was wall anchoring motif. GBS strains carry one shown to interact directly with glucos- of two srr gene alleles, designated srr1 aminoglycans (GAGs) on brain endothelium, (Samen et al., 2007) and srr2 (Seifert et al.,
Group B Streptococcus Meningitis 125
2006), which are similar in architecture but once present in the CNS to amplify the
show only limited homology (< 20% identity). host response and disease progression.
Expression of the Srr-2 protein seems to be Alternatively, early molecular interactions of
restricted to serotype III and ST-17 strains GBS with the BBB and subsequent barrier
(Seifert et al., 2006). Targeted mutagenesis of a disruption may alter cellular polarity. It has
GBS Δsrr1 mutant resulted in a marked been demonstrated that GBS is capable of
reduction in HMBEC adherence and invasion intercellular transit across an epithelial cell
(van Sorge et al., 2009). The srr1 genes in GBS barrier, where the bacterium co-localized
serotypes Ia, Ib and V, as well as srr2 in the with junctional protein complexes (Soriani et
serotype III ST-17 clone, each contributed to al., 2006). Recent data also indicate that GBS
HBMEC invasion in vitro, and Srr-1 promoted infection disrupts tight junctional complexes
BBB penetration and the development of GBS in brain endothelium (Kim et al., 2012). An
meningitis in a mouse model of haema- overall reduction in the distribution of the
togenous meningitis (van Sorge et al., 2009). primary BBB tight junction protein, zona
Srr-1 contributes to GBS attachment to occludin (ZO)-1, was observed by immuno-
HBMECs via the direct interaction of its fluorescence during GBS infection. Further
binding region (BR) with human fibrinogen evidence demonstrated a decrease in protein
(Seo et al., 2012). Studies using recombinant levels of ZO-1 and additional tight junction
Srr1-BR established a direct protein inter- protein, occludin, following GBS infection
action with the amino acid sequence 283–410 compared with the uninfected control (Kim et
of the fibrinogen A chain. Structural al., 2012). Whether these interactions act to
predictions indicated that the conformation disrupt tight junctional complexes in brain
of Srr1-BR resembles that of other related endothelium and result in a non-polarized
bacterial proteins that bind to fibrinogen distribution of proteins on the BBB plasma
through a ‘dock, lock and latch’ (DLL) membrane, and/or promote GBS intercellular
mechanism (Ponnuraj et al., 2003). The DLL transit across the BBB, remains to be
mechanism results when fibrinogen engages investigated.
a binding cleft between two domains, N2 and Host factors involved in arachidonic
N3. At the ligand ‘dock’, the flexible acid metabolism also contribute to
C-terminal extension of the N3 domain (the penetration of the BBB by GBS (Maruvada et
‘latch’) changes conformation, so that it al., 2011). Pharmacological inhibition and
‘locks’ the ligand in place, and forms a gene deletion demonstrated that host
-strand complex with the N2 domain. cytosolic phospholipase A2 (cPLA2)
Deletion of the predicted latch domain of contributes to type III GBS invasion of
Srr1-BR abolished the interaction of Srr1-BR HBMEC monolayers and penetration into
with fibrinogen. In addition, a mutant GBS the brain in vivo. The mechanism probably
strain lacking the Srr-1 latch domain exhibited involves lipoxygenated metabolites of
reduced binding to HBMECs, and was arachidonic acid, specifically cysteinyl
significantly attenuated in an in vivo model of leukotrienes released by cPLA2 as well as
meningitis (Seo et al., 2012). Further studies protein kinase C (PKC). GBS penetration
are required to determine if similar into the CNS in cPLA2−/− mice was
mechanisms for fibrinogen binding and significantly lower than the penetration of
disease progression occur in Srr-2-encoding wild-type mice. However, the magnitudes of
strains. bacteraemia were similar between cPLA2−/−
and wild-type mice, suggesting that
decreased penetration was not the result of
Intercellular invasion (paracytosis)
decreased levels of blood-borne bacteria.
The host integrins, ECM components and Interestingly, cPLA2 deletion did not affect
glycosaminoglycans involved in GBS–BBB GBS penetration into non-brain organs, such
interactions all preferentially localize to the as the kidneys and spleen, as similar numbers
basolateral surface of polarized endothelium. of bacterial counts were recovered from
Thus, GBS may interact with these factors cPLA2−/− and wild-type mice (Maruvada126 V. Nizet and K.S. Doran
et al., 2011). The basis for this selective role of It is clear that the GBS β-haemolysin/
host cPLA2 in GBS neurotropism is cytolysin (β-h/c) toxin contributes much to
unknown. the observed disease pathology. Haemolysin
expression has been shown to directly
damage brain endothelial cells (Nizet et al.,
GBS disruption of the BBB
1997), leptomeninges (meningioma cells) and
The host inflammatory response to GBS astrocytes (Alkuwaity et al., 2012) and
contributes significantly to the pathogenesis of primary neurons (Reiss et al., 2011). Infection
meningitis and CNS injury. A vascular with wild-type GBS and β-h/c+ cell-free
distribution of cortical lesions in neonatal rats extracts induced cell death, whereas chal-
with GBS meningitis indicates that lenge with β-h/c-deficient (β-h/c−) mutant
disturbances of cerebral blood flow contribute strains and β-h/c− extracts did not. Notably,
to neuronal damage (Kim et al., 1995). astrocytes were more sensitive to the
Inflammation of individual brain vessels can cytotoxic effects of infection than meningioma
lead to focal lesions, whereas diffuse cells (Alkuwaity et al., 2012). In neurons, cell-
alterations of cerebral blood flow cause free extracts of GBS β-h/c toxin induced
generalized hypoxic/ischaemic injury and apoptosis in a time- and concentration-
cerebral oedema (Kim et al., 1995). GBS induces dependent fashion; electron microscopy of
nitric oxide (NO) in brain endothelial cells the neurons showed condensation, shrinkage
(Glibetic et al., 2001) and in microglial cells, and partial fragmentation of cells and nuclei
resulting in neuronal destruction (Lehnardt et as well as damage to mitochondria (Reiss et
al., 2006). Furthermore, arteriolar dysfunction al., 2011). In these studies, GBS β-h/c-induced
is associated with the presence of oxygen free cell death could not be prevented by caspase
radicals thought to be a by-product of inhibitors, nor was caspase activity detected
infiltrating neutrophils (McKnight et al., 1992). in neurons, consistent with observations in
Intraventricular inoculation of newborn other cell types including macrophages.
piglets with GBS results in an early sharp rise Haemolysin expression has also been shown
in CSF tumour necrosis factor- TNF- to promote the development of meningitis
levels, followed shortly by prostaglandin in vivo (Doran et al., 2003; Lembo et al., 2010).
release and subarachnoid inflammation (Ling In a murine model of haematogenous
et al., 1995). In the neonatal rat model of meningitis, mice infected with β-h/c− mutants
meningitis, TNF- production by astrocytes, exhibited lower mortality and decreased
microglia and infiltrating leucocytes con- brain bacterial counts compared with mice
tributes to apoptosis of hippocampal neurons infected with the corresponding wild-type
(Bogdan et al., 1997) and further increases in GBS strains (Doran et al., 2003). Similarly,
BBB permeability (Kim et al., 1997). Recent mutants that lack the negative repressor of
studies have verified the levels of cytokine/ β-h/c, CovR (for control of virulence),
chemokine, myeloperoxidase (MPO) activity, exhibited high levels of toxin expression and
oxidative stress and disruption of the BBB in an increased ability to penetrate the BBB in
the hippocampus and cortex of neonate Wistar vivo (Lembo et al., 2010). Multiple studies
rats, following GBS meningitis (Barichello have demonstrated that the lipid dipalmitoyl-
et al., 2011). In the neonate brain, the phosphatidylcholine (DPPC) provides pro-
hippocampus, mainly, produced higher levels tection against β-h/c-mediated injury in
of cytokine/chemokine in the early phase of various host cells (Nizet et al., 1996; Doran et
infection, while MPO activity remained al., 2002b; Hensler et al., 2008; Alkuwaity et
elevated at 4 days post-infection in both brain al., 2012). DPPC might preserve the host cell
structures (Barichello et al., 2011). Interestingly, membrane by providing phospholipid
in the neonatal rat, simultaneous intracisternal replacement during pore formation and/or
administration of dexamethasone with GBS by direct neutralization by binding to toxin
challenge markedly reduced the magnitude of itself. The therapeutic potential of surfactant
subarachnoid inflammation, vasculopathy phospholipids in GBS meningitis requires
and neuronal injury (Kim et al., 1995). further study.Group B Streptococcus Meningitis 127
9.3 GBS Activation of a CNS pathogen may result in over-activation of BBB
Inflammatory Response endothelium, leading to increased inflam-
mation that may compromise BBB integrity or
The first comprehensive microarray analysis cause neuronal damage.
of the BBB endothelium transcriptional Several GBS factors have been implicated
response to a pathogen was examined during in promoting BBB activation. Infection of
GBS infection, revealing the induction of a HBMECs with a GBS strain lacking β-h/c
specific set of 80 genes, which function toxin markedly reduced expression of genes
together to orchestrate neutrophil recruitment, involved in the immune response, while an
activation and enhanced survival (Doran et al., unencapsulated strain generally induced
2003). The most highly induced genes, similar or greater expression levels for the
interleukin (IL)-8, CXCL1 and CXCL2, all same subset of genes (Doran et al., 2003).
belong to the CXC chemokine family, which Neutrophil migration across polar HBMEC
acts mainly on cells of neutrophil lineage. IL-8 monolayers was stimulated by GBS and its
is the most potent chemotactic factor for β-h/c through a process involving IL-8 and
neutrophils because it has a high affinity for ICAM-1. Furthermore, cell-free bacterial
both of the chemokine receptors (CXCR1 and supernatants containing β-h/c activity
CXCR2) expressed on neutrophils, and it induced IL-8 release, thus identifying this
further stimulates neutrophil respiratory toxin as a principal provocative factor for BBB
burst, degranulation and adherence to activation (Doran et al., 2003). In more recent
endothelial cells. These chemokines have been studies, additional microarray experiments
isolated from the CSF of patients with bacterial have demonstrated that the similar gene
meningitis, and IL-8 may be an important profile in HBMECs is effected by CovR
biomarker to differentiate acute bacterial regulation, which can result in high β-h/c
meningitis from aseptic meningitis (Pinto expression (Lembo et al., 2010) and PilA
Junior et al., 2011). Other GBS-induced expression (Banerjee et al., 2011). Infection of
HBMEC genes related specifically to CNS HBMECs in vitro with multiple PilA-deficient
neutrophil recruitment were ICAM-1, which GBS strains resulted in less IL-8 protein
when upregulated leads to the enhanced secretion compared with the respective wild-
adhesion of neutrophils to the brain type parental strains, and treatment of
endothelium, and granulocyte–macrophage HBMECs with recombinant PilA protein
colony-stimulating factor (GM–CSF), which induced IL-8 transcription, suggesting that
increases neutrophil migration across brain PilA is both necessary and sufficient to activate
endothelium. Absent during GBS infection of the BBB response (Banerjee et al., 2011).
HBMECs was the induction of strong pro- Infection in vivo with the PilA-deficient strain
inflammatory cytokines, such as TNF- or resulted in delayed mortality, decreased
IL-1. These data suggest that the BBB neutrophil infiltration and bacterial CNS
represents much more than a physical barrier dissemination, and less expression of KC, the
to GBS, and also performs a sentinel function murine homologue of IL-8 (Banerjee et al.,
by recognizing the threat of infection and 2011). These results indicate that GBS PilA
initiating a CNS-protective innate immune directly promotes IL-8 secretion and
response. In the case of blood-borne bacteria, a functional neutrophil signalling pathways in
specific BMEC gene expression programme vivo, resulting in neutrophil recruitment
for neutrophil recruitment and activation is during active GBS infection, which may
generated, with the absence of the concurrent function in tandem or concurrently with the
production of broader spectrum cytokines β-h/c toxin to promote disease progression.
(e.g. TNF-, IL-1) that could provoke a wider These findings also demonstrate an
or unchecked pattern of inflammatory association between leucocyte trafficking and
activation potentially harmful to critical CNS BBB permeability and increased GBS
structures. However, the timing and penetration of the CNS, suggesting that
magnitude of the neutrophil recruitment polymorphonuclear leucocyte (PMN)-
response is critical for the outcome of infection. mediated damage of the BBB has a significant
Continued exposure and invasion of the role in the pathogenesis of GBS meningitis.128 V. Nizet and K.S. Doran
9.4 Conclusions RgfA/C activates the fbsB gene encoding major
fibrinogen-binding protein in highly virulent
Advances in microbial genetics, tissue culture CC17 clone Group B Streptococcus. PLoS One
6, e14658.
systems and small-animal challenge models
Alkuwaity, K., Taylor, A., Heckels, J.E., Doran, K.S.
have enhanced our understanding of the
and Christodoulides, M. (2012) Group B
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and the host response to this potentially life- meningeal cells and astrocytes in vitro. PLoS
threatening infection. New model systems One 7, e42660.
using zebrafish (Patterson et al., 2012) and Baker, C.J. and Edwards, M.S. (2001) Infectious
Drosophila (Baron et al., 2009; Chang et al., Diseases of the Fetus and Newborn Infant. W.B.
2011) promise the contribution of host Saunders, Philadelphia, PA.
genetics to enrich our understanding of host– Banerjee, A., Kim, B.J., Carmona, E.M., Cutting,
GBS interactions. Comparative genomic and A.S., Gurney, M.A., Carlos, C., Feuer, R.,
Prasadarao, N.V. and Doran, K.S. (2011)
systems-level bioinformatics studies have
Bacterial pili exploit integrin machinery to
revealed strain evolution associated with
promote immune activation and efficient blood–
hypervirulence and CNS disease potential, brain barrier penetration. Nature Com-
including specific candidate gene and munications 2, 462.
regulatory systems that promote bloodstream Barichello, T., Lemos, J.C., Generoso, J.S.,
survival, HBMEC interactions and activation Cipriano, A.L., Milioli, G.L., Marcelino, D.M.,
of host inflammatory responses. Genomics Vuolo, F., Petronilho, F., Dal-Pizzol, F., Vilela,
has led to the development of reverse and M.C. and Teixeira, A.L. (2011) Oxidative stress,
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Research 36, 1922–1930.
(Nuccitelli et al., 2011). In addition, genomics
Baron, M.J., Wong, S.L., Nybakken, K., Carey, V.J.
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as therapeutic or immuno-prophylactic meningitis. A clinical and pathological study of
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Acknowledgements streptococcal meningitis. Journal of Infectious
Diseases 176, 693–697.
The authors thank their respective laboratory Brochet, M., Couve, E., Zouine, M., Vallaeys, T.,
members and researchers whose work has Rusniok, C., Lamy, M.C., Buchrieser, C., Trieu-
not been discussed in detail or reviewed Cuot, P., Kunst, F., Poyart, C. and Glaser, P.
elsewhere. Work on the BBB and GBS (2006) Genomic diversity and evolution within
meningitis in K.S. Doran’s laboratory is the species Streptococcus agalactiae. Microbes
supported by funding from the NIH/NINDS and Infection 8, 1227–1243.
Brouwer, M.C., Tunkel, A.R. and van de Beek, D.
(grant no RO1NS051247).
(2010) Epidemiology, diagnosis, and anti-
microbial treatment of acute bacterial meningitis.
Clinical Microbiology Reviews 23, 467–492.
Campbell, J.R., Baker, C.J. and Edwards, M.S.
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