29 Pathogenesis and 

Pathophysiology
of Bacterial Infections of the CNS
Loic Le Guennec1,2 and Sandrine Bourdoulous1
1
Inserm, U1016, Institut Cochin, CNRS, UMR8104, Paris University, Paris, France
2
La Pitie‐Salpetriere Hospital, APHP, Paris, France

PCR polymerase chain reaction

Abbreviations
Pcho Phosphorylcholine
pIgR polymeric immunoglobulin
ACP alpha C protein
receptor
β2AR beta‐2‐adrenergic receptor
PMNL polymorphonuclear leukocyte
BBB blood‐brain barrier
SCID severe combined
CNS central nervous system
immunodeficient
CSF cerebrospinal fluid
SOL space‐occupying lesion
E. coli Escherichia coli
Sfb streptococcal
EMPRINN extracellular matrix metallo­
fibronectin‐binding
proteinase inducer for
S. pneumoniae Streptococcus pneumoniae
N. meningitidis
Srr serine‐rich repeat
EoD early‐onset disease
T4P type IV pili
fHBP factor H‐binding protein
TNF‐α tumor necrosis factor alpha
GBS group B Streptococcus
TRL toll‐like receptor
H. influenzae Haemophilus influenzae
ZO1 zona occludens 1
HvgA hypervirulent GBS adhesin
IL interleukin
ICP intracranial pressure Introduction
L. monocytogenes Listeria monocytogenes
LoD late‐onset disease Bacterial infections of the CNS pose a unique
LTA lipoteichoic acid ­challenge to physicians because of their potential
N. meningitidis Neisseria meningitidis morbidity and mortality and inherent difficulties
MMP matrix metalloproteinase involved in their treatment. Rapid diagnosis and
MRI magnetic resonance image prompt treatment are mandatory, but despite
M. tuberculosis Mycobacterium tuberculosis advances in  antibacterial therapy and vaccines,
PAF platelet‐activating factor complications frequently occur, resulting in an

Infections of the Central Nervous System: Pathology and Genetics, First Edition. Edited by Fabrice Chrétien,
Kum Thong Wong, Leroy R. Sharer, Catherine (Katy) Keohane and Françoise Gray.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.

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Infections of the Central Nervous System
unfavorable outcome in a high proportion of
patients and neurological sequelae in survivors [1].
The most important infections are meningitis,
encephalitis, and brain abscesses. They differ con­
siderably from systemic infections, due to the par­
ticular structure and function of the CNS.
Structurally, the CNS is covered by three protective
membranes: the skull, the spine, and the meninges.
Additionally the blood‐brain barrier (BBB) consti­
tutes a selective filter that controls the entry of toxic
compounds or pathogens [2]. The presence of a
lymphatic vasculature within the brain is still con­
troversial [3]. Consequently, leukocytes (i.e. granu­
locytes and T and B cells) stay within blood vessels
and usually do not enter healthy brain tissue.
Within the CNS, host defenses rely on innate
immune cells including parenchymal (microglia)
and nonparenchymal macrophages and perivascu­
lar blood‐derived monocytes [4]; these defenses
are not sufficient to control bacterial proliferation
and pathogenicity. During CNS infection or dis­
ease, peripheral blood immune cells cross the BBB
and reach the nervous system parenchyma. The
host inflammatory response then plays a central
role in contributing to local complications.
Depending on the pathogen involved, systemic
complications such as septic shock, pneumonia,
and disseminated intravascular coagulation also
contribute to a poor outcome.
In this chapter, we will briefly review the most
common clinical and pathological features of bac­
terial CNS infections.
Clinical presentation of bacterial
infections of the CNS
The clinical features of CNS infections depend on
the bacterial agent, the site of infection, and host
characteristics, such as underlying risk factors and
immune status. In a patient who is febrile, the com­
mon neurologic manifestations suggesting CNS
infection are disturbance of consciousness, behav­
ioral changes, headache, symptoms of raised
intracranial pressure (ICP), seizures, and focal
neurologic deficits. Overall, fever associated with
neurological impairment should suggest one of the
following medical emergencies.
280
Acute meningitis
Acute meningitis is the most frequent and life‐
threatening bacterial infection of the CNS, charac­
terized by an acute purulent infection of the
meninges [5]. It is usually caused by Streptococcus
pneumoniae, Neisseria meningitidis, or Haemophilus
influenzae in children and adults and by Escherichia
coli and group B Streptococcus (GBS) during the
neonatal period. Listeria monocytogenes can affect
neonates and patients who are immunocompro­
mised. The main route of infection is hematoge­
nous, but the responsible bacteria can also spread
contiguously from adjacent tissues or gain entry as
a complication of trauma, surgery, or developmen­
tal malformations. Usually, patients present with
fever associated with acute or subacute meningeal
syndromes (i.e. headache, stiff neck, Kernig and
Brudzinski signs, nausea, vomiting, and phono‐ or
photophobia) [5].
Assuming clinical guidelines for safe lumbar punc­
ture are followed, in a patient with suspected menin­
gitis, rapid examination of the cerebrospinal fluid
(CSF) is the cornerstone of diagnosis. Typical CSF
examination for bacterial meningitis shows a cloudy
and turbid fluid with pleocytosis (white blood cell
count >10 cells/mm3) with marked predominance of
polymorphonuclear leukocytes (PMNL) (>50%), low
or absent glucose (<40% of serum glucose), and an
elevated protein levels (>50 mg/dl). Direct micros­
copy with appropriate stains for organisms, followed
by culture and antibiotic sensitivity tests, allow
identification of the responsible bacteria. Blood
­
­culture is also useful, especially when CSF sampling is
precluded by significant raised ICP.
Chronic meningitis
Chronic meningitis is defined as an inflammatory
CSF profile and meningitis symptoms that persist
for at least one month. Worldwide, the main caus­
ative pathogen is Mycobacterium tuberculosis, the
agent responsible for tuberculosis, which contin­
ues to cause high morbidity and mortality. It is fre­
quently associated with spinal tuberculosis and
CSF analysis reveals elevation of PMNL early in
the infection, later followed by lymphocytic men­
ingitis with high CSF protein. Early detection of
M. tuberculosis in the CSF of patients with
­tuberculous meningitis still remains a challenge
 Pathogenesis and Pathophysiology of Bacterial Infections of the CNS  Chapter 29

for clinicians, mainly because of the lack of rapid,

efficient and practical detection methods. Isolation
of M. tuberculosis from the CSF is complicated as
culture is unacceptably slow and requires special­
ized laboratory safety procedures (see Chapter 35).
Polymerase chain reaction (PCR) assays were
found to be insensitive at detecting M. tuberculosis
in CSF samples, and interferon gamma (IFN‐γ)
release assays are not recommended for diagnosis
of active tuberculous disease [6].
Less commonly, other intracellular or extracel­
lular bacteria can cause chronic meningitis. These
include Brucella spp., which causes brucellosis (see
Chapter  38); Treponema pallidum, the causative
agent of syphilis (see Chapter  37); and Borrelia
burgdorferi, which causes Lyme disease (see
Chapter  38). For these pathogens, CSF analysis
usually shows a lymphocytic meningitis, and direct
microscopy and culture are negative because they
cannot be cultivated in culture media. Diagnosis is Figure 29.1  Axial computed tomography (CT) brain scan
showing right frontal sinusitis in an adult with past medical
mostly based on the patient’s history, positive serol­
history of open right frontal bone fracture in childhood,
ogy, and extraneurological symptoms.
complicated by right frontal lobe brain abscess. Bacterial culture
In all cases, repeat CSF examination is required of the abscess was positive for Streptococcus pneumoniae.
over time to survey bacterial infection and inflam­
mation within the meninges.
The abscess location depends on the site of the
Brain abscess initial infective focus: frontotemporal regions for
Abscess is the second‐most frequent infection of the sinuses, cerebellar and temporal regions for the
the CNS and the most frequent infective cause of middle ear, and frontoparietal regions for hema­
intracranial space‐occupying lesion (SOL). When togenous spread. Post‐traumatic abscesses occur at
formed, it is a focal brain parenchymal suppura­ the sites of craniocerebral injury. Multiple abscesses
tive infection, generally enclosed by a capsule of tend to be found at the gray and white matter junc­
granulation tissue. At the early stage, following tions and should suggest an embolic cause, such as
local vascular injury after inoculation of bacteria, an infective endocarditis (Figure 29.2).
brain abscess is characterized by cerebritis with Neurological examination shows clinical signs of
PMNL infiltration, edema, and a perivascular raised ICP associated with focal neurologic signs
fibrinous exudate causing raised ICP. The sequen­ (i.e. seizures, alteration of behavior or conscious­
tial changes in the following days are described in ness, sensorimotor deficit). Forty percent of
detail in Chapter 31. patients have fever and only 25% have a meningeal
In 75% of cases, the abscess is single. Micro­ syndrome. Magnetic resonance imaging (MRI)
organisms reach the brain (i) from an adjacent cranial shows a ring‐enhancing SOL associated with
or extracranial focus of infection, (ii) from distant foci edema and mass effect. Imaging can also demon­
via the bloodstream, or (iii) when introduced by strate complications such as subdural empyema or
trauma (Figure  29.1) or via a congenital defect (see epidural abscess. In the presence of significant
Chapter 31 for more details). Infections of paranasal raised ICP, lumbar puncture is contraindicated.
sinuses, ears, lungs, and odontogenic foci were Neurosurgical drainage and antibiotic therapy fol­
regarded as the sources of infection in approximately lowing microbiological analysis are usually neces­
70% in a series of 45 cases [7]. sary for treatment.

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Infections of the Central Nervous System

Figure 29.2  Brain magnetic resonance image (MRI) (axial plane, T2 fluid attenuated inversion recovery [FLAIR] sequence) showing
multiple embolic abscesses within the right frontal lobe, the basal ganglia, and the brainstem in a patient with Streptococcus pneumoniae
endocarditis.

The causative agent depends on the primary site surgery) or by bacteremia (Figure 29.3) because of
of infection and on host factors, particularly the distant‐site infections (endocarditis, furuncle, or
immune status. Immunosuppression is a well‐ soft‐tissue abscess) [8].
established risk factor and is reported in 80% of The clinical picture is similar to spinal cord com­
patients. The most common pathogens are anaero­ pression with intense spinal pain, radicular signs,
bic streptococci (e.g. Streptococcus milleri) and and paraparesis associated with sensory, bladder,
anaerobic Gram‐negative bacilli (e.g. Bacteroides and bowel sphincter disturbance. MRI shows a
fragilis). In patients who are immunocompetent, biconvex extra‐axial lesion outlined by the bony
when the primary source is a dental infection, a skull or vertebra. On T1‐weighted sequences the
mixed growth of bacteria is commonly found in
the brain abscess. In patients who are immuno­
compromised, other species such as Actinomyces
israelii and Nocardia spp. can be responsible for
brain abscesses. L. monocyogenes can also cause
abscesses within the brainstem with or without
meningitis. Finally, intracranial tuberculous
abscesses (tuberculomas) are an uncommon mani­
festation of CNS tuberculosis. The initial empirical
antibiotic treatment depends on the immunologi­
cal status of the host, adjusted following bacterial
identification and results of sensitivity.

Epidural abscess
Infection of the epidural space is rare. It is located
in the virtual space between the skull (or the spine)
and the outer layer of the dura mater. These infec­
tions mainly affect immunocompromised adults Figure 29.3  Cervicomedullary magnetic resonance image (MRI)
older than 50 years of age. The abscess is caused by (sagittal plane, T1 sequence) showing anterior epidural abscess
an adjacent infection (i.e. osteomyelitis, or follow­ contiguous with cervical spondylodiscitis resulting from embolism
ing cranial or spinal trauma, epidural anesthesia, or in a patient with Staphylococcus aureus endocarditis.

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 Pathogenesis and Pathophysiology of Bacterial Infections of the CNS  Chapter 29
lesion is iso‐ or hypodense and hyperdense on T2‐
weighted sequences with peripheral or diffuse con­
trast enhancement. Bacterial identification can be
from blood cultures, from the primary site of infec­
tion, from CSF, or by ultrasound‐guided or neuro­
surgically acquired biopsy from the epidural abscess.
Treatment consists of urgent surgical drainage
together with broad spectrum antibiotics against
Staphylococcus aureus, Streptococcus spp., and
Gram‐negative rod‐shaped bacteria and anaer­
obes. M. tuberculosis can also be responsible for
epidural abscess, as a complication of tuberculosis
of the spine (Pott’s disease).
Subdural empyema
The mode of development and bacteriology of
subdural empyema is similar to that of epidural
abscess. Subdural empyema is a collection of pus
between the dura and the subarachnoid mem­
brane. The subdural space is traversed by veins
and divided into several large compartments.
Subdural empyema is usually caused by aerobic
and anaerobic bacteria, which reach the subdural
space from veins draining the skull. The primary
sites of infection are mainly in the sinuses, fol­
lowed by mastoid and middle ear infections.
Usually, the empyema is located above the tento­
rium or adjacent to the falx cerebri and rarely in
the spinal canal. Treatment includes antibiotics
and surgical intervention.
Ventriculitis
Ventriculitis generally occurs as a complication of a
previous CNS bacterial infection such as meningi­
tis or a brain abscess that ruptures into the cerebral
ventricles. The main complication is hydrocepha­
lus. Clinical symptoms are due to raised ICP
because of hydrocephalus.
Bacterial invasion of the CNS
In the past few decades, our knowledge of the
mechanisms of bacterial invasion of the CNS has
greatly improved because of basic research and
experimental animal models.
The routes of entry by which bacteria access the
CNS are: (i) hematogenous dissemination, by
crossing the BBB transcellularly, paracellularly or
in infected phagocytes (the so‐called Trojan horse
mechanism); (ii) by retrograde axonal transport
to  the brain via cranial or peripheral nerves; and
(iii) by direct invasion.
The most common route of entry to the CNS for
extracellular bacteria is via the bloodstream. Most
pathogens responsible for CNS infections can asymp­
tomatically colonize skin and mucosa of healthy indi­
viduals. These pathogens can reach the bloodstream,
survive within the blood, and ultimately cross the
BBB. Extracellular pathogens that can cause menin­
gitis are well‐adapted to survive in the extracellular
environment: they can all resist killing by PMNLs or
complement and can obtain the ferric iron required
for their growth and survival. Sustained bacteremia
seems to be required to cause meningeal invasion [9].
The duration of bacteremia is also important, for
example in H. influenzae meningitis, both the density
and duration of bacteremia correlate with meningeal
invasion [10]. Furthermore, autopsies have shown
that most extracellular bacteria can interact directly
with brain endothelial cells [11]. A dense bacteremia
probably increases the likelihood of bacterial interac­
tion with the components of CNS barriers, which is a
prerequisite for meningeal invasion.
Numerous in vitro studies using brain‐derived
endothelial cell lines expressing tight junctions have
investigated how circulating bacteria responsible
for meningitis interact with the BBB. These studies
have identified bacterial adhesins and their specific
endothelial cell receptors such as platelet activating
factor receptor for S. pneumoniae [12] or CD147
(also known as Basigin or extracellular matrix met­
alloproteinase inducer [EMPRINN]) for N. menin-
gitidis [13]. Relevant in vivo experimental models
have been set up to study how pathogens such as E.
coli, GBS, S. pneumoniae, or N. meningitidis can
reach the CNS, but the precise site or method of
entry by which they cross into the CSF is still
unknown. The choroid plexus is suggested as one
site where bacteria could cross. If this were the case,
bacterial meningitis might be expected to be associ­
ated with ventriculitis, which is not always present.
Another theory suggests bacteria cross the BBB
through postcapillary perforating venules because
of their proximity to the subarachnoid space.
Bacteria crossing the endothelial monolayer at this
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Infections of the Central Nervous System

site would be close to the Virchow Robin space. nasopharyngeal mucosa in asymptomatic individu­
Also, the low blood flow in these venules could als but is responsible for otitis media, sinusitis, and
facilitate bacterial adhesion to endothelial cells [11]. for severe invasive infections, such as pneumonia,
There are several hypotheses as to how bacteria bacteremia, and acute meningitis (Figure  29.4).
cross the endothelial cell barrier. One possibility is a Findings regarding the pathophysiology of pneu­
facilitated transport occurring during diapedesis of mococcal meningitis are either derived from brain
infected leukocytes, but extracellular bacteria autopsies or from animal models.
responsible for meningitis probably do not use this To reach the meninges, pneumococci have to
route to cross the BBB because several studies have escape ear‐nose‐throat or respiratory mucosal
shown a specific interaction between bacteria and defenses and either cause sinusitis or mastoiditis,
endothelial cells [13]. Many studies hypothesized with local spread through the skull, or survive
that bacterial adhesion to endothelial cells induces within the bloodstream and be carried into the
intracellular signaling that could cause disruption CNS (Figure 29.5). The pneumococcal capsule pro­
of intercellular tight junctions, allowing bacteria to vides protection against phagocytosis, comple­
cross between or across cells (transcytosis) of the ment‐mediated immunity, and opsonophagocytic
endothelial monolayer. Transcytosis across this killing. The capsule also reduces pneumococcal
monolayer has been demonstrated for S. pneumo- capture by neutrophil extracellular traps and inter­
niae [14], E. coli [15], GBS [16], and through human feres with innate immune responses by masking
umbilical vein endothelial cells for H. influenzae several toll‐like receptor (TLR) ligands associated
[17]. In vitro, although N. meningitidis internalized with the pneumococcal cell wall. These include
in human brain microvascular endothelial cells lipoteichoic acid and lipopeptides. Furthermore, its
[18], the pathway used by meningococci to cross ability to form biofilms is important in naso­
endothelial cells is still debated. Another hypothesis pharyngeal colonization, pneumonia, and otitis
is that bacteria exert a direct cytotoxic effect result­
ing in disruption of the endothelial barrier, but BBB
leakage because of bacterial cytotoxicity might be
expected to cause subarachnoid hemorrhage, which
is a rare event in bacterial meningitis. These patho­
gens seem to respect the architecture of the BBB
[19]. Inflammation may also play a role in bacterial
entry into the CNS. The innate immune response
induced by bacteremia, with or without septic
shock, may increase BBB permeability, thereby pro­
moting bacterial entry into the CNS.
The following section describes the most fre­
quent bacteria responsible for acute meningitis and
their respective pathophysiological mechanisms
leading to mucosal colonization, dissemination,
and crossing of the BBB (Table 29.1).

S. pneumoniae
S. pneumoniae (pneumococcus) is an alpha‐hemolytic
Gram‐positive extracellular coccus. It frequently
resides in the upper respiratory tract of humans and
other related mammalian species. It is the most
frequent organism responsible for community‐
acquired bacterial meningitis worldwide, affecting
young children and the elderly. It can colonize the
Figure 29.4  Bronchioalveolar lavage (BAL), stained with
May‐Grünwald Giemsa, showing diplococci within altered
polymorphonuclear neutrophils in a patient with acute
community‐acquired pneumonia and clinical meningitis. Blood
cultures were positive for Gram‐positive cocci. The patient also
had purpura fulminans with coagulopathy, so lumbar puncture
was contraindicated. BAL and blood cultures were positive for
Streptococcus pneumoniae.

284
 Table 29.1  Main bacterial pathogens responsible for acute meningitis.

Streptococcus Neisseria Haemophilus

pneumoniae meningitidis Influenzae type b Group B Streptococcus Escherichia coli K1 Listeria monocytogenes

Type of bacteria Gram‐positive Gram‐negative Gram‐negative rod Gram‐positive diplococcus Gram‐negative rod Gram‐positive rod shaped
diplococcus diplococcus shaped shaped
Population Between 2 months Between 2 months and Children <5 years <3 months <3 months <3 months, and adults
affected and 5 years, and 5 years, and young
>50 years adults
Risk factors Splenectomy or Alternative and terminal Insufficient access to Maternal carriage and Maternal carriage and Ingestion of contaminated
functional complement vaccines prematurity prematurity food in pregnant women
hyposplenia pathway deficiencies or patients with
immunocompromise
Carriage site/ Nasopharynx, lung Nasopharynx Nasopharynx Rectal or vaginal Rectal Digestive tract
Site of entry
Virulence factors Capsule, CbpA, Capsule, LOS, Type IV Capsule, gA1 protease Capsule, lipotechoic acid, Capsule, O‐LPS, OmpA, Capsule, InIA, InIB,
PCho (PAF), pili LOS, Hib Type I pili, ScpB, type 1 fimbriae, Listeriolysin O
pneumolysin Omp FbsA, b‐hemolysin CNF1
Host cell pIgR, laminin CD147, β2‐adrenergic Mucin, Lactoferrin Fibronectin, fibrinogen Laminin receptor E‐cadherin, Met
receptors receptor, PAF receptor and laminin
receptor

CbpA, Choline‐binding protein A; CNF1, cytotoxic necrotizing factor 1; LOS, lipooligosaccharide; LPS, lipopolysaccharide; Omp, outer member protein; PAF, platelet‐activating factor;
PCho, phosphorylcholine (mimics the chemokine PAF); plgR, polymeric immunoglobulin receptor.

0004466174.INDD 285 18­12­2019 13:29:05

Infections of the Central Nervous System

Autolysin LytA
Streptococcus and Pneumolysin release
pneumoniae

PCho
CbpA
PAFr
pIgR Laminin
Blood

Endothelial cell

Cell wall degradation

Brain

Transcellular pathway
Paracellular pathway

Legend:

Streptococcus pneumoniae Platelet-activating factor receptor (PAFr) Junction disruption

Autolysin LytA and Pneumolysin Polymeric immunoglobulin receptor (pIgR)

Phosphorylcholine (PCho) Laminin

Figure 29.5  Mechanism of CNS invasion by Streptococcus pneumoniae. S. pneumoniae adheres to endothelial cells by the bacterial
choline‐binding protein CbpA (also called PspC, SpsA or Hic), which binds to human cell laminin and polymeric immunoglobulin receptor
(pIgR), and bacterial phosphorylcholine (PCho), which mimics the chemokine platelet‐activating factor (PAF) and binds to the cell receptor
PAF receptor (PAFr), enabling transcytosis across the endothelium. Additional release of pneumococcus autolysin LytA and pneumolysin
promote cell wall degradation and endothelial monolayer disruption, allowing paracellular bacterial invasion.

media. Pneumolysin, a key virulence factor a polymeric immunoglobulin receptor (pIgR) at

secreted by S. pneumoniae, binds to cholesterol in
cell membranes. This pore‐forming toxin, pro­
duced by virtually all clinical isolates of S. pneumo-
niae, contributes significantly to its virulence by
inducing tissue damage and plays a role in biofilm
formation [20].
The first step in pneumococcal invasion is the
interaction between the bacterial choline‐binding
protein CbpA (also called PspC, SpsA or Hic) and
the cell surface of nasopharyngeal or respiratory
epithelial cells. This interaction promotes bacte­
rial transcytosis across the epithelial barrier [20].
Once in the bloodstream, bacterial CbpA binds
brain endothelial cells through laminin receptor.
Pneumoccocci can also anchor to human epithe­
lial and endothelial cells through an interaction
between bacterial phosphorylcholine (PCho),
which mimics the chemokine platelet‐activating

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 Pathogenesis and Pathophysiology of Bacterial Infections of the CNS  Chapter 29
factor (PAF) and binds its cell receptor (PAF
receptor [PAFr]), the first known host cell recep­
tor for S. pneumoniae. This interaction promotes
bacterial transcytosis, through a clathrin‐medi­
ated endocytosis in brain endothelial cells [20].
Pneumococcus has an additional important prop­
erty of undergoing autolysis, characterized by cell
wall degradation by a peptidoglycan hydrolase
(autolysin Lyt A), leading to pneumolysin release
(and its associated virulence). In a microvascular
endothelial cell culture model, pneumococci
expressing pneumolysin could breach endothelial
cells, whereas mutant pneumococci deficient in
pneumolysin could not [21]. This effect on brain
endothelial cells could potentially induce apopto­
sis and disruption of BBB, favoring bacterial entry
into the CNS. Pneumolysin impairs PMN leuko­
cyte activity and also activates different proin­
flammatory signaling pathways, which may
accentuate brain inflammation and neuronal
damage. Both CbpA and pneumolysin seem
essential for pneumococcal pathogenesis. In mice,
immunization against CbpA and pneumolysin
can protect against pneumococcal infection and
prevent nasopharyngeal carriage [22]. Finally,
nasal cavity infection in a mouse model suggests
that pneumococci may enter the brain directly by
axonal transport through olfactory nerves [23].
Teichoic acid in the pneumococcal cell wall can
interact with gangliosides, so it has been sug­
gested that pneumococcal carriage can induce
olfactory tissue infection and bacterial entry into
the brain in the absence of bacteremia. However,
these colonizing bacteria fail to cause extensive
brain infection. Whether these events occur in
humans remains to be proven, so further studies
are required to determine the precise pathophysi­
ology of pneumococcal meningitis.
N. meningitidis
N. meningitidis (meningococcus) is an extracellular
Gram‐negative diplococcus. It is one of the most
virulent bacteria, responsible for 10% of meningitis
deaths. Systemic complications, such as septic shock,
purpura fulminans, and disseminated intravascular
coagulation, contribute to the unfavorable outcome.
N. meningitidis is restricted to humans; it is a fre­
quent nasopharynx commensal with asymptomatic
carriage in healthy individuals in 8‐ 20% of the popu­
lation and up to 25% in children [24]. Meningococci
are transmitted by respiratory secretions, saliva, or by
inhalation of contaminated aerosol droplets.
Nasopharyngeal acquisition may be transient, lead to
colonization, or result in invasive disease. Blood‐
borne infections can rapidly progress to septic shock.
As meningococci adhere to, and proliferate in, sys­
temic microvessels, vascular colonization leads to
abnormal inflammation and coagulation, endothe­
lial dysfunction and, in severe cases, to vascular leak­
age associated with the typical extensive necrotic
purpuric rash. Interaction with brain microvessels
allows bacteria to cross the BBB, reach the meninges,
and cause meningitis (Figure  29.6), while brain
endothelial cell junctions are relatively intact with no
signs of hemorrhage or thrombosis [13].
The prerequisite for meningococcal pathogenic­
ity is its interaction with the nasopharyngeal epi­
thelial surface and transfer across this mucosal
barrier to reach the circulation [25]. Mucosal colo­
nization and crossing mechanisms are poorly
described. Once in the bloodstream, many viru­
lence factors enable bacterial growth and immune
escape from host effectors and the complement
system. They include the iron chelation systems,
the polysaccharide capsule, the sialylated lipooligo­
saccharide, and factor H‐binding protein (fHBP).
Pathogenesis is also linked to some bacterial
genetic factors (e.g. expression of a gene encoding a
hemoglobin receptor and the expression of a fila­
mentous prophage were detected at a higher fre­
quency in pathogenic isolates than in carriage
isolates) [26].
However, meningococcal pathogenicity princi­
pally relies on the capacity to interact with human
microvessels. This was elegantly demonstrated in
vivo in a severe combined immunodeficient
(SCID) mouse model, grafted with human skin.
The grafted human vessels connected with the
mouse vasculature and remained functional.
Following infection with N. meningitidis, circulat­
ing meningococci specifically colonized human
endothelial cells within the grafts and promoted
vascular lesions similar to purpuric lesions in
humans [27]. Mouse vessels were not colonized
and remained intact. The model also demonstrated
that pathogenic capsulated meningococci required
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Infections of the Central Nervous System

Neisseria
meningitidis

Type IV Pili Type IV Pili

CD147 β2AR
Blood

Endothelial cell
Intercellular junction
Brain disruption

Paracellular pathway
Legend:

Neisseria meningitidis CD147 Junction disruption

Type IV Pili B2-Adrenergic receptor (β2AR)

Figure 29.6  Mechanism of CNS invasion by Neisseria meningitidis. Type IV pili (T4P) of N. meningitidis interact with endothelial cell
receptor CD147, leading to the activation of both β2‐adrenergic receptor (β2AR) and downstream signaling cascades. In vitro, infection
promotes the disruption of intercellular junctions, which could favor paracellular bacterial entry into the CNS across the blood‐brain barrier.

type IV pili (T4P) to colonize and induce vascular
damage. T4P are long dynamic filamentous struc­
tures extending from the bacterial surface through
the capsule. Nonpiliated mutants failed to target
human graft vessels or induce vascular damage
[27]. This model also showed that the vascular cell
wall provided an environment for meningococcal
multiplication promoting a sustained bacteremia
and mouse lethality. These studies highlighted the
importance of pilus‐mediated vascular coloniza­
tion in the development and outcome of meningo­
coccal sepsis.
At the molecular level, to colonize human
endothelium, meningococcal T4P interact with
two key endothelial cell receptors: CD147 (also
called EMMPRIN or Basigin), a member of the
immunoglobulin superfamily, and endothelial
beta‐2‐adrenergic receptor (β2AR) leading to its
bias activation [25]. β2AR activation promotes
local recruitment and activation of cytoskeleton‐
associated and signaling proteins. This results in
(i) forming protrusions of the apical plasma
membrane, which stabilize bacterial colonies at
the endothelial cell surface (Figure  29.7), and

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 Pathogenesis and Pathophysiology of Bacterial Infections of the CNS  Chapter 29

Scanning electron microscopy Nuclei CD147

5 µm

Ezrin Actin Merge

10 µm

Figure 29.7  Mechanism of CNS invasion by Neisseria meningitidis. Right panel: Upon adhesion to human brain endothelial cells
(hCMEC/D3 cells) meningococci proliferate at the endothelial cell surface forming compact microcolonies observed by scanning electron
microscopy (left panel). Subsequently, local membrane protrusions form which stabilize bacterial colonies at the endothelial cell surface
upon shear stress. The protrusions result from local changes in endothelial cytoskeletal architecture. Immunofluorescence microscopy
(right panels) shows surface microcolonies, with local accumulation of the endothelial cell receptor CD147, of the membrane‐cytoskeleton
linker Ezrin and of cortical actin polymerization, all involved in protrusion formation.

(ii) ­opening of intercellular ­junctions that con­
tribute to vascular changes [25]. Colonization
also favors endothelial cell survival, the expres­
sion of adhesion molecules, and the secretion of
cytokines [28].
Although the affinity of T4P for CD147 and
β2AR is weak, these receptors are assembled into
multimers [29], and CD147 expression on brain
endothelial cells is strong, thus enhancing
­avidity [13]. The low levels of shear stress in the
cerebral microcirculation also favor bacterial
adhesion [11]. Other meningococcal factors can
reinforce or modulate adhesion (detailed
in [30]).
Colonization of brain capillaries in the suba­
rachnoid space, the parenchyma and the choroid
plexus suggested that N. meningitidis actively
crosses the BBB by disrupting cell‐cell junctions.
In vitro studies indicate that meningococcal
­adhesion to human brain endothelium induces
signaling events leading to altered endothelial
permeability. N. meningitidis actively disrupts
cell‐cell junctions and promotes sequestration of
cell‐cell junction molecules, such as VE‐cadherin,
zona occludens 1 (ZO1), or claudin 5, to the sites
of bacterial adhesion [25]. Meningococcus also
activates matrix metalloproteinase 8 (MMP8)
production, which promotes proteolytic cleavage
of the tight junction protein occludin, favoring
cell detachment. Because N. meningitidis infec­
tion is specific to humans, there is no relevant in
vivo animal model of CNS invasion to test
whether the same process occurs in vivo at the
human BBB.

289
Infections of the Central Nervous System

GBS because of small numbers of alveolar macrophages

GBS is a Gram‐positive extracellular coccus and is
the main cause of bacterial meningitis in babies
younger than two months of age. Contamination
usually occurs by maternal‐fetal transmission from
the birth canal at the time of delivery. Mothers are
frequently asymptomatic. About 30–70% of neo­
nates born to mothers with GBS‐colonization
become transiently colonized by their mother’s
organisms. Neonates, particularly if premature,
have an increased risk for bacterial meningitis
and PMNL and low levels of immunoglobulin A/
immunoglobulin G (IgA/IgG). The most common
route of entry is inhalation or ingestion of amniotic
fluid contaminated by the maternal genital tract,
which itself can be contaminated by pelvic exami­
nation during the peripartum period. Bacteria then
cross the fetal respiratory or gastrointestinal
mucosa, proliferate in the blood, and enter the CNS
(Figure  29.8). GBS is responsible for early‐onset
disease (EoD), typically occurring within the first

Group B
Streptococcus
Srr2
ST-17

Plasminogen

FbsA HvgA
PilA
Fibrinogen Glycosamino-
Sfb Collagen
Fibronectin glycan α2β1Integrin
Blood

Endothelial cell

β-hemolysin Cell wall degradation

Brain

Transcellular pathway
Paracellular pathway
Legend:

Group B Streptococcus ST-17 Srr2 Glycosaminoglycan Junction disruption

β-hemolysin Plasminogen Collagen

FbsA Fibrinogen PilA

Sfb
Fibronectin A2β1 Integrin
HvgA

Figure 29.8  Mechanism of CNS invasion in Group B Streptococcus (GBS) meningitis. GBS adheres to brain endothelial cells through
interaction of the adhesins Srr2, HvgA, and FbsA with components of the extracellular matrix (ECM). GBS adhesin pilA binds to collagen
and indirectly interacts with α2β1 integrins at the endothelial cell surface. Following interaction, GBS can invade brain endothelial cells,
allowing transcellular crossing of the blood‐brain barrier (BBB) by an unknown mechanism. Additional release of β‐hemolysin promotes
cell wall degradation and endothelial monolayer disruption, allowing bacterial invasion through a paracellular pathway.

290
 Pathogenesis and Pathophysiology of Bacterial Infections of the CNS  Chapter 29
week of life, with pneumonia, bacteremia, and
sometimes meningitis. Late‐onset disease (LoD)
occurs in infants up to two months of age, with
fewer symptoms related to bacteremia and a higher
incidence of meningitis. A single clone, GBS ST‐17,
is strongly associated with LoD [31].
GBS possesses multiples adhesins [31], includ­
ing lipoteichoic acid (LTA), pili, serine‐rich repeat
(Srr) proteins, streptococcal fibronectin‐binding
protein (Sfb), the surface protein hypervirulent
GBS adhesin (HvgA), found in hypervirulent
ST‐17 strains, and alpha C protein (ACP; encoded
by bca), which binds to glycosaminoglycan. These
components enable GBS to interact with various
human cell types, including vaginal epithelium,
placental membranes, airways, and brain endothe­
lial cells. Adhesion to epithelial cells is mediated by
lipoteichoic acid associated with the bacterial wall,
and by GBS surface proteins. The pilus protein
PilA, Srr1, Sfb, and ACP also mediate GBS interac­
tion with basement membrane components. GBS
binds to extracellular matrix components, includ­
ing fibronectin, fibrinogen, and laminin, which
facilitate mucosal colonization [31]. This interac­
tion is mediated by ScpB, a homolog of the Lra1
adhesin family, and by FbsA, a surface‐anchored
protein. ST‐17 strains specifically express Srr2, a
cell wall‐anchored protein, which binds plasmino­
gen and plasmin, increases bacterial survival from
phagocytic killing and bacterial persistence in a
murine model of meningitis. This suggests that
Srr2 hijacks ligands of the host coagulation system,
contributing to GBS dissemination, invasiveness,
and ultimately to meningitis [32].
GBS has also developed strategies to penetrate
and cross host cell barriers and to avoid immuno­
logical clearance and inflammatory response
because its sialylated capsular polysaccharide limits
host complement activation and phagocytosis.
Animal models and in vitro culture systems have
shown that GBS can invade brain endothelial cells,
supporting the transcellular theory of BBB crossing.
Recent data support a Snail1‐dependent mecha­
nism of BBB disruption and penetration [33]. GBS
can promote the induction of host transcriptional
repressor Snail1, which impedes expression of tight
junction genes, facilitating tight junction disruption
and promoting BBB permeability to allow bacterial
passage. In addition, GBS β‐hemolysin/cytolysin is
directly cytolytic for human brain endothelial cells
and may contribute to BBB disruption.
E. coli
E. coli is an extracellular Gram‐negative bacillus. It
is the second cause of meningitis in neonates and
the leading cause in premature infants [34]. Rectal
carriage of E. coli in women of childbearing age is
up to 50%. Maternal‐fetal colonization affects about
70% of their newborns, without necessarily causing
pathogenicity. About 80% of E. coli strains isolated
from pregnant women and newborns possess the
K1 capsular polysaccharide antigen that protects
the bacterial cell from immune attack. E. coli K1
meningitis starts with gastrointestinal mucosa colo­
nization, followed by invasion, survival, and prolif­
eration within the blood [35]. E. coli K1 can induce
high‐level bacteremia [35]. At the brain level, E. coli
K1 binds to cerebral capillaries via bacterial surface
structures such as OmpA and type 1 fimbriae. The
interaction induces host cell actin cytoskeleton
rearrangement and microvilli‐like protrusions that
facilitate bacterial internalization. E. coli K1 is then
stored in cell vacuoles and reaches the subarach­
noid space after its release at the basal membrane of
microvascular endothelial cells.
L. monocytogenes
L. monocytogenes is a facultative intracellular
Gram‐positive bacillus, which can survive at freez­
ing temperatures and proliferates at very low
(refrigeration) temperatures. For this reason, it is
associated with foodborne illness. L. monocy-
togenes crosses the intestinal and fetoplacental
barriers via the interaction of bacterial proteins
InIA and InIB with cell surface proteins E‐cadherin
and Met respectively [36]. L. monocytogenes
spreads through the CNS by the diapedesis of
infected monocytes (Trojan horse mechanism)
across the BBB, and by direct invasion of endothe­
lial cells [36]. After entering endothelial cells, the
bacteria escape from phagosomes via a hemolysin
called listeriolysin O or LLO, a pore‐forming mol­
ecule. Once in the cytoplasm, L. monocytogenes
highjacks actin cytoskeleton of the infected cell for
its own propulsion (comet tails), and spreads in
adjacent cells. Direct intra‐axonal spread along
291
Infections of the Central Nervous System
lower cranial nerves and within the brain has been
demonstrated in animal models and may also be
important in human listeria brainstem and rhom­
boencephalitis [37].
Inflammation
Inflammation plays a central role during bacterial
CNS infection. Although mandatory for host pro­
tection against pathogens, inflammation is also
responsible for several crucial steps of bacterial
invasion and inflammation‐induced adverse
events, such as BBB rupture, CSF cytokine produc­
tion, leukocyte invasion in the CSF, and neuronal
injury.
A wide range of innate sensors are expressed by
all neuronal and nonneuronal cells within the CNS.
Locally, in response to bacterial invasion, endothe­
lial, glial, and resident immune cells produce pro­
inflammatory factors, including the cytokines
tumor necrosis factor alpha (TNF‐α), interleukin
(IL)‐1β, IL‐8/CXCL‐8, and IL‐6. These initiate an
inflammatory cascade and attract immune cells.
Matrix metalloproteinases (MMPs) are also pro­
duced, which degrade the extracellular matrix,
allow cell migration, and increase BBB permeabil­
ity [38]. In the inflammatory state, adhesion mole­
cules such as VCAM‐1 and ICAM‐1 are expressed
at the endothelial cell surface, facilitating leukocyte
adhesion [39]. PMNL are locally recruited in the
acute phase, and a mix of T and B cells, monocytes,
and dendritic cells in the chronic stage; all are
required for microbial control. Several portals of
entry into the brain exist for inflammatory cells,
including the fenestrated vasculature within the
subarachnoid space and the choroid plexus, across
epithelial and ependymal cells of the choroid
plexus or astrocyte endfeet of BBB.
Inflammation affects cerebral blood flow during
bacterial infection of the CNS. In acute meningitis,
endothelin, a strong vasoconstrictor, is secreted by
brain endothelial cells, and contributes to cerebral
blood flow reduction and ischemia [40]. Reactive
oxygen species (ROS) and reactive nitrogen species
produced by granulocytes, endothelial cells, and
microglial cells are responsible for vascular damage
within the brain [41].
292
Conclusions
Many clinical syndromes are encountered in CNS
infections. Accurate diagnosis and prompt treat­
ment are mandatory. The pathophysiology is com­
plex, contributed to by both direct bacterial damage
and the host inflammatory response. A full under­
standing of these infections may help the design of
new therapies to block bacterial invasion and
reduce inflammation response‐induced injuries.
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