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S225

Pathophysiology of Bacterial Meningitis: Mechanism(s) of Neuronal Injury


W. Michael Scheld,1,2 Uwe Koedel,4 Barnett Nathan,3 Division of Infectious Diseases, Departments of 1Internal Medicine,
2
and Hans-Walter Pfister4 Neurosurgery, and 3Neurology, University of Virginia School
of Medicine, Charlottesville; 4Department of Neurology,
Ludwig Maximilians University, Munich, Germany

No bacterial disease has undergone a more dramatic change in epidemiology during the
past decade than acute bacterial meningitis. This review describes the changing epidemiology
and considers some important recent observations that contribute to our understanding of
the pathogenesis and pathophysiology of meningitis. The major focus is on the mechanisms
of neuronal injury and the pathophysiologic concepts responsible for death and neurologic
sequelae. In recent years, experimental studies have amplified our understanding of the sub-
stantial body of evidence that now implicates cytokines and chemokines, proteolytic enzymes,
and oxidants in the inflammatory cascade leading to tissue destruction in bacterial meningitis.
The molecular mechanisms responsible for oxidant-induced neuronal injury in meningitis are

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explored in some depth. Genetic targeting and/or pharmacologic blockade of the implicated
pathways may be a future strategy for therapeutic adjunctive measures to improve outcome
and may hold substantial promise, in concert with antimicrobial agents, in humans with acute
bacterial meningitis.

From the first description of meningococcemia and menin- and about half the survivors have neurologic and other sequelae
gococcal meningitis, before identification of the etiologic or- of the disease [4].
ganism (by Vieusseux in 1806) until the early twentieth century, Over the past four decades, clinical and neuropathologic
bacterial meningitis was considered a nearly uniformly fatal studies have documented the clear association between bacterial
disease, although some patients with meningococcal meningitis meningitis and brain edema formation, impairments of cere-
survived without antimicrobial therapy. The advent of various brospinal fluid (CSF) hydrodynamics, increased intracranial
experimental procedures followed by antisera therapy directed pressure, seizure activity, arterial and venous cerebral vascular
against meningococci reduced mortality rates during World insults (that may relate to death), and other neurologic sequelae.
War I, but the introduction of sulfonamides and penicillins Therefore, during the past 1520 years, emphasis has been on
along with other antimicrobial agents heralded the reduction a greater understanding of the pathogenesis and pathophy-
in morbidity and survival possible with modern antimicrobial siology of bacterial meningitis in an attempt to improve out-
therapy. Despite these achievements and the introduction of come [5].
several new antimicrobial agents with in vitro activity against It is apparent that the host immune response is incapable of
the major meningeal pathogens plus some limited improvement controlling infection within the central nervous system (CNS),
in diagnostic assays, bacterial meningitis remains associated particularly the CSF within the subarachnoid space, and that
with unacceptably high morbidity and mortality [1]. this host inflammatory response may be responsible for many
Endemic meningitis is relatively unusual in developed coun-
adverse events during bacterial meningitis [6, 7]. A very complex
tries although epidemic meningitis occurs with considerable fre-
and integrated series of events involving host cytokines, che-
quency in resource-limited settings. Explosive epidemics of me-
mokines, proteolytic enzymes, and oxidants appears to be re-
ningococcal meningitis have continued to affect the so-called
sponsible for meningitis-induced brain dysfunction. This has
meningitis belt of sub-Saharan Africa. The most recent epi-
resulted in the search for adjunctive therapies for bacterial men-
demic, which began in 1996, has resulted in over 300,000 cases
ingitis, including corticosteroids.
and 30,000 deaths [2]. At present, exclusive of epidemics, about
In this brief review, we highlight recent epidemiologic trends
1.2 million cases of bacterial meningitis are estimated to occur
in bacterial meningitis worldwide and consider the current con-
annually worldwide with 135,000 deaths [3]. Bacterial menin-
cepts of the pathogenesis and pathophysiology of this syndrome
gitis is now a top 10 infectious cause of death worldwide,
with an emphasis on the identification of promising targets for
adjunctive therapy. Some of these concepts have been reviewed
Reprints or correspondence: Dr. W. Michael Scheld, University of Virginia recently [810]. The pathogenesis of bacterial meningitis, in-
Health System, Dept. of Medicine, Division of Infectious Diseases, PO Box
cluding colonization of the nasopharynx by the pathogen, mi-
801342, Charlottesville, VA 22908 (wms@virginia.edu).
crobial invasion into the intravascular space and survival within
The Journal of Infectious Diseases 2002; 186(Suppl 2):S22533
2002 by the Infectious Diseases Society of America. All rights reserved.
the bloodstream, microbial entry mechanisms into the CNS,
0022-1899/2002/18611S-0015$15.00 survival within the subarachnoid space, and host and/or en-
S226 Scheld et al. JID 2002;186 (Suppl 2)

vironmental factors contributing to susceptibility to invasive (particularly serotype C:2a:P1:2) into a population in which
disease are reviewed more extensively elsewhere [8]. serogroup B strains had been the predominant causes of en-
demic disease.
As documented in Scandinavia, susceptibility to invasive me-
Changing Epidemiology of Acute Bacterial Meningitis ningococcal disease is largely due to acquisition of a new vir-
ulent strain in a host without circulating bactericidal antibody
No bacterial infection worldwide has undergone a more spec-
tacular evolution in epidemiology than acute meningitis since against the causative organism [14]. The United Kingdom in
1990. The introduction of Haemophilus influenzae conjugate November 1999 was the first country to launch vaccination
vaccines (Hib) in the United States and western Europe has against group C meningococcal disease, and a rapid decrease
resulted in a decline in the incidence of invasive H. influenzae in the incidence of this syndrome (including clusters) is expected
infections by 90% [1]. As a result, Streptococcus pneumoniae (see Public Health Laboratory Service [UK] annual report
and Neisseria meningitidis are the major causes of bacterial 19881999 and highlights 1999/2000). Infants and young adults
meningitis in these regions. Furthermore, a dramatic change in aged 1517 years are targeted, and this strategy may be ap-
the epidemiology has resulted from these achievements such plicable to other regions with clusters of meningococcal disease.

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that the median age of onset of acute bacterial meningitis has Serogroup A (/C) vaccines are currently available. Wide-
increased from age 9 months to age 25 years in the United spread use of these vaccines in the meningitis belt is warranted
States [1]. Similarly, the availability of conjugate pneumococcal to reduce morbidity and mortality while more complex poly-
vaccines has led to the near total elimination of invasive pneu- saccharide-protein conjugate vaccines are phased into use.
mococcal disease, including bacteremia and meningitis, in Another disturbing epidemiologic trend is the emergence of
young children in regions adopting this approach. Nevertheless, antimicrobial resistance among meningeal pathogens. At pre-
most countries in developing regions have not added the Hib sent the most serious is the emergence of penicillin resistance
vaccine to the standard vaccine repertoire offered to children, (along with resistance to multiple other antimicrobial agents)
because of cost. As a result, an estimated 350,000700,000 chil- among S. pneumoniae. Antimicrobial usage, particularly b-lac-
dren worldwide still die of invasive Hib disease each year. tams in low concentrations for prolonged periods, leads to se-
In 1999, the Global Alliance for Vaccines and Immunization lection for resistance among pneumococci in children and
(GAVI) was formed with the mission to ensure adequate vac- adultsboth the carrier state and invasive disease; nevertheless,
cination of every child worldwide against preventable diseases. penicillin resistance varies widely among developed countries
Within 18 months of its inception, GAVI committed more than [15]. In addition to this selective pressure, other factors con-
$600 million to the vaccine fund in 36 developing countries tribute to the development and spread of resistant pathogens,
over 5 years to foster deployment of vaccines such as Hib in including an extension of their spectrum of resistance and re-
susceptible populations (http://www.vaccinealliance.org). While sistance genes among diverse microorganisms and mutations
the ultimate effect of pneumococcal conjugate vaccines on the in common genes [16].
epidemiology of bacterial meningitis is not known, it is hoped Resistance to penicillin involves mutations in 1 or more pen-
that uniform vaccination, such as recently introduced into the
icillin-binding proteins (PBP) in S. pneumoniae, reducing the
United States, will nearly totally eliminate this form of men-
affinity for penicillin and related antibiotics. These mutations
ingitis, which is associated with the highest mortality and mor-
are usually present in the transpeptidase penicillin-binding do-
bidity rates. Again, cost will be an issue in resource-limited
main. Multiple mutations are required to result in high-level
settings.
resistance among PBP variants [17]. The genes that encode for
According to criteria set forth in the 1992 Institute of Med-
the altered PBP are called mosaics, since they consist of native
icine report on emerging infectious diseases, meningococcal
pneumococcal DNA mixed with fragments of foreign DNA,
meningitis and meningococcemia are emerging infectious dis-
eases [11]. The interdependence of the worldwide community presumably derived from streptococci normally resident in the
and travel have enabled the spread of meningococcal strains healthy human nasopharynx. This foreign DNA has been in-
from the Indian subcontinent to Saudi Arabia during the Haj corporated by the pneumococci into the chromosome. The
to the sub-Saharan African meningitis belt and the onset of worldwide spread of penicillin resistance among S. pneumoniae
explosive epidemics. Clusters of meningococcal disease have appears to be due to dissemination of several clones carrying
also been reported from multiple regions in recent years [12, altered PBP genes. In addition, chloramphenicol resistance has
13]. Clusters are defined as two or more clinical or confirmed appeared among meningococci. If this trend continues on a
cases of meningococcal disease arising within 12 months in the worldwide basis, the consequences will be devastating as chlo-
same defined settinghousehold, nursery/playground, primary ramphenicol is widely used as the antimicrobial of choice in
school, secondary school, university or college [11, 13]. This resource-limited settings, especially in the sub-Saharan African
phenomenon has been reported in North America and Europe meningitis belt. Penicillin resistance among meningococci is also
following the introduction of new serotypes of serogroup C spreading (e.g., from 9% of strains in 1998 to 25% of strains
JID 2002;186 (Suppl 2) Pathophysiology of Bacterial Meningitis S227

in 2001 in Ontario, Canada), but the impact on therapeutic of recent studies follow (for a more detailed discussion of path-
strategies is not known. ogenesis, see [8]).
The clinical outcome of acute bacterial meningitis depends
on multiple factors including the socioeconomic status of the
patient (developed vs. developing countries), age, pathogen, Pathophysiology of Bacterial Meningitis
and the clinical characteristics and laboratory manifestations
Various bacteria including the major meningeal pathogens
of the acute infection. For example, the case fatality rate for
(e.g., S. pneumoniae) undergo autolysis under harsh conditions
H. influenzae type B meningitis in recent reviews has been about
such as exposure to antimicrobial agents and/or growth to sta-
5%, [1], a figure similar to that of meningococcal meningitis in
tionary phase. Autolysis consists of self-digestion of the cell
the same report. Conversely, the mortality rate associated with
wall by peptidoglycan hydrolyases termed autolysins. At least
pneumococcal meningitis is about 20% versus 15%30% for
3 autolysins are recognized in pneumococci, but the major au-
Listeria monocytogenes in recent years [1]. About 30% of the
tolysin is the N-acetyl-muramoyl-l-alanine amidase (LytA) [24].
survivors of pneumococcal meningitis develop long-term se-
Activation of LytA and autolysis result in the release in sub-
quelae such as hearing loss, neuropsychologic impairment, and
capsular bacterial components including peptidoglycan, lipo-
neurologic deficits [18].

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teichoic acid, bacterial DNA, and pneumolysin.
The case fatality rate of S. pneumoniae meningitis varies dra-
Mechanisms of immune activation. Various cell wall prod-
matically by agewith a case fatality rate of !10% in children
ucts of meningeal pathogens are well-known inducers of the
but about 40% in those 50 years old. These results apply only
inflammatory host response. The inflammatory response in the
to developed countries. In developing regions, 60%80% of chil-
subarachnoid space characteristic of acute purulent meningitis
dren and adults with pneumococcal meningitis still succumb to
can be reproduced by the intracisternal challenge with whole
the infection [18, 19]. The risk of death is greatest for those
heat-killed unencapsulated pneumococci, their isolated cell
with neurologic complications during the acute illness (e.g.,
walls, lipoteichoic acid, or peptidoglycan, but not by the in-
cerebrovascular insults, hydrocephalus, brain edema, and in-
jection of heat-killed encapsulated strains or isolated capsular
volvement of large intracranial blood vessels). Brain infarction
polysaccharide [25, 26]. Exact mechanisms of immune activa-
with severe irreversible cerebral damage and an increase of in-
tion by pneumococcal cell wall products remain poorly under-
tracranial pressure result from cerebrovascular involvement of
stood, but recent in vitro studies suggest that the first step in
both arteries and veins. These complications may be diagnosed
immune activation is binding of peptidoglycan and/or lipotei-
by computerized tomography, magnetic resonance imaging or
choic acid to the pattern recognition receptor membrane CD14
angiography, or transcranial Doppler sonography, but these
(mCD14). mCD14 is not a transmembrane molecule and thus
modalities are not widely available in resource-limited settings.
by itself cannot transmit the activating signal into the cell.
A second step in immune activation is necessary and this
potentially occurs through the toll-like receptor-2 (TLR-2).
Pathogenesis of Bacterial Meningitis Coexpression of CD14 and TLR-2 in Chinese hamster ovary
fibroblasts confers responsiveness to pneumococcal peptido-
While not the focus of this review, recent studies have en- glycan and heat-killed S. pneumoniae as evidenced by inducible
hanced our understanding of the pathogenesis of bacterial men- translocation of the nuclear transcription factor NF-kB [27].
ingitis among the major pathogens. To cause disease, the path- These studies also suggest that pneumococci stimulate both a
ogen must, in the absence of a neurosurgical procedure or CSF TLR-2dependent and a TLR-2independent pathway; how-
leak, colonize the nasopharynx, traverse the nasopharynx into ever, in a model of pneumococcal meningitis, TLR-2deficient
the bloodstream, survive host defense mechanisms in the in- mice responded to live pathogens virtually to the same extent
travascular space, invade the blood-brain barrier (BBB), and as wild type mice (Koedel et al., unpublished data). Leukocyte
survive and replicate in the subarachnoid space, producing dis- infiltration into the subarachnoid space and brain mRNA ex-
ease. Multiple interactions between the host and the organism pression of proinflammatory cytokines and chemokines did not
have been described in recent years and it is of interest that the differ between TLR-2deficient and wild type mice inoculated
major meningeal pathogens have several similarities in common with live pneumococci. It appears that mechanisms other than
(e.g., asymptomatic carriage in the nasopharynx, the ability to binding of pneumococcal cell wall products to TLR-2 play a
cause devastating disease, phosphoryl choline moieties, poly- central role in the induction of the host immune response during
saccharide capsules, IgA proteases, and certain physiologic fea- pneumococcal meningitis. It appears that both TLR-2depen-
tures such as phase variations, DNA transformation, and au- dent and independent (pneumolysin) pathways are sufficient
tolysis) [2022]. to cause inflammation in the absence of the other, but in vivo
Our laboratories have concentrated on S. pneumoniae; else- both are likely activated.
where in this issue the elegant work of Kim [23] on the traversal TLR-2independent immune activation may be mediated at
of Escherichia coli across the BBB is reported. A few highlights least in part by the pneumococcal toxin pneumolysin. Pneu-
S228 Scheld et al. JID 2002;186 (Suppl 2)

molysin stimulates the production of inflammatory mediators in and ERK-2/ERK-1 MAPK activities [38]. These same MAPKs
vitro including tumor necrosis factor (TNF)-a, interleukin (IL)- are also activated when rat or human astrocytes are stimulated
1b, and IL-6 [28]. Pneumolysin is also an inducer and/or activator with various pneumococcal cell wall fragments. In addition,
of enzymes such as phospholipase A2, COX-2, and inducible pneumococci activate NF-kB in undifferentiated human and
nitric oxide synthase (iNOS). However, in a rabbit meningitis mature murine monocytes [39]. Although the signaling path-
model, a pneumolysin-deficient pneumococcal strain resulted in ways involved in immune inactivation only recently became a
an inflammatory response similar to that induced by injection of major focus of research activity, a rat model of pneumococcal
the wild type strain, suggesting that pneumolysin is not essential meningitis showed a marked increase in NF-kB activity. Phar-
for the induction of meningeal inflammation [29]. macologic inhibition of NF-kB led to a significant reduction of
Another potential trigger of immune activation during acute host inflammatory responses as evidenced by lower CSF leu-
meningitis is bacterial DNA released during bacterial autolysis. kocyte and IL-6 concentrations [40]. It appears that NF-kB is
Bacterial DNA has substantial immune stimulatory effects on a central transcriptional activator of many genes that encode
B, NK, and dendritic cells and on monocytes and macrophages proteins, host factors, or both involved in the pathophysiology
[30, 31]. The activity of bacterial DNA is mediated by unme- of pneumococcal meningitis, including cytokines, chemokines,
thylated CpG motifs, in particular base contexts. In fact, when and adhesion molecules.

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mice or rats are injected intracisternally with bacterial DNA Proinflammatory cytokines. Multiple cytokines play an im-
or unmethylated CpG oligonucleotides, meningitis developed portant regulatory role in the control of inflammation. TNF-
within 12 h. Bacterial DNA appears to initiate CNS inflam- a, IL-1b, and IL-6 are major early response cytokines that
mation by stimulation of macrophages and proinflammatory trigger, often in synergy, a cascade of inflammatory mediators,
products such as TNF-a [32]. TLR-9 is absolutely required for including other cytokines, arachidonic acid metabolites, che-
cellular responses to CpG DNA, and TLR-9deficient mice mokines, and reactive nitrogen and oxygen intermediates [41].
show no response to CpG DNA (inflammatory cytokine pro- Multiple cell types within the CNS including cerebromicrovas-
duction from macrophages, maturation of dendritic cells, or cular endothelial cells, astrocytes, and microglia produce all 3
proliferation of splenocytes) [33]. TLR-9deficient mice are also cytokines. Increased concentrations of these cytokines have
completely resistant to the lethal effects of CpG DNA without been detected in CSF samples from patients with acute bacterial
production of serum proinflammatory cytokines. Thus, the role meningitis and concentrations of IL-1b, but not IL-6 and TNF-
of the CpG DNATLR-9 pathway for immune activation in a, are associated with significantly worse disease outcome or
acute bacterial meningitis deserves further evaluation. In sum- disease severity [42].
mary, subcapsular bacterial components act as inducers of the Brain mRNA and protein expression of IL-1b, IL-6, and
host inflammatory response in acute bacterial meningitis, but TNF-a are markedly up-regulated in rodents during the acute
the host receptor systems and downstream elements of signal stage of experimental pneumococcal meningitis [43, 44]. Recent
transduction are still largely unexplored. studies with genetically engineered mice provide further insight
Intracellular signal transduction pathways. For meningeal into the role of acute phase cytokines in the pathophysiology
pathogens, the major inflammatory stimuli are lipopolysac- of pneumococcal meningitis. For example, brain bacterial titers
charide (LPS) and peptidoglycan for gram-negative and gram- were not affected by either TNF-a or TNF receptor deficiency
positive organisms, respectively. These inflammatory stimuli ac- in murine models of CNS infection. Furthermore, leukocyte
tivate I-kB kinase NF-kB pathways and 3 mitogen-activated recruitment into the subarachnoid space was not affected by
protein kinase (MAPK) pathways: extracellular signal-regu- TNF deficiency. In contrast, mice with targeted disruption of
lated kinases (ERK) 1 and 2, c-Jun N-terminal kinase (JNK), TNF receptors p55 and p75 had decreased meningeal inflam-
and p38 [34, 35]. As a result of activation of these signaling mation [45]. It appears that other TNF receptor ligands (e.g.,
pathways, a variety of transcription factors are activated: NF- lymphotoxin-a) must contribute to the induction and/or main-
kB (p50/p65) and activator protein-1 (cFos/cJun), which co- tenance of the inflammatory response during pneumococcal
ordinate the induction of many genes encoding a variety of meningitis. Intracisternal inoculation of pneumococci caused a
inflammatory mediators [36]. three-fold increase in CSF leukocyte concentrations in IL-6de-
Soluble peptidoglycan strongly activates ERK-1 and -2 in ficient mice when compared with wild type controls. Increased
the mouse macrophage cell line RAW264-7 and moderately CSF pleocytosis is thought to result from higher brain expres-
activates JNK, while weak activation of p38 MAPK is ob- sion of the potent neutrophil chemoattractant macrophage in-
served. In contrast, LPS strongly activates all of these kinases, flammatory protein (MIP)-2 [8]. These observations are similar
suggesting a similar but not identical activation of signal trans- to those in animal models of endotoxin-induced lung injury
duction pathways by these major inflammatory mediators of and endotoxemia, where IL-6 appears to control the extent of
meningeal pathogens [37]. the inflammatory response by down-regulating the expression
Pneumococcal cell wall components release inflammatory of chemokines and/or proinflammatory cytokines.
mediators by mouse microglia, which is dependent on both p38 No data have been presented on IL-1b or IL-1 receptor de-
JID 2002;186 (Suppl 2) Pathophysiology of Bacterial Meningitis S229

ficiency and the pathophysiology of acute bacterial meningitis. ering, triggering, firm adhesion, and emigration) are involved
The role of caspase (Casp)-1 in the pathophysiology of pneu- in this adhesion cascade. The selectin family of adhesion mol-
mococcal meningitis has been the subject of recent experiments. ecules (P-, E-, L-selectin) mediates tethering and promotes leu-
Casp-1 plays a central role in the generation of mature IL-1b kocyte rolling under flow conditions.
and IL-18 [46]. Casp-1 mRNA and protein expression is up- Firm adhesion of leukocytes to the endothelium is mediated
regulated in the brain during experimental pneumococcal men- by a family of integrins. Integrin activation requires a triggering
ingitis; this up-regulated activation is associated with increased step mediated by a proinflammatory cytokine (e.g., IL-1b) and
levels of IL-1b [8]. Furthermore, depletion of the Casp-1 gene chemokines (e.g., IL-8), complement products, and bacterial
and/or pharmacologic blockade of Casp-1 attenuates the men- cell wall components. Leukocyte integrins, once activated, bind
ingitis-induced increase in IL-1b. A significant reduction in NF- to endothelial cell count receptors. Macrophage antigen 1
kB activity, brain TNF-a, MIP-1a, and MIP-2 expression, and (MAC-1; CD11b/CD18) is the predominant integrin involved
CSF pleocytosis was also observed [8]. The Casp-1IL-1b sig- in neutrophil binding to the activated endothelial cell. Inter-
naling pathways play a crucial role in the induction and am- cellular adhesion molecule (ICAM)-1, an immunoglobulin-like
plification of the host inflammatory response during pneu- molecule, exhibits low constitutive levels on the cell surface of
mococcal meningitis. TNF-a and IL-1b also stimulate the the resting endothelium but is markedly induced by exposure

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expression of chemokines and adhesion molecules, which fur- to inflammatory stimuli and is the most important endothelial
ther facilitate the passage of leukocytes from the circulation ligand for MAC-1. After firm adhesion to endothelial cells,
into the subarachnoid space. leukocytes migrate along a chemotactic gradient, mediated by
Chemokines. Based on the number and spacing of the con- chemokines into the subarachnoid space.
served N-terminal cysteines, chemokines are currently subdi- Partial inhibition of CSF leukocyte accumulation in the sub-
vided into 4 distinct subfamilies: the CXC or a, CC or b, CX3C arachnoid space was noted in P-selectindeficient mice during
or g, and C or d subfamilies [47]. The CXC chemokines are experimental meningitis, whereas mice doubly deficient in P-
further divided into 2 groups depending on the presence of the and E-selectins showed dramatic and nearly complete inhibition
ELR motif preceding the first cysteine. Despite this classifica- of leukocyte accumulation into the subarachnoid space [50].
tion, within each chemokine subfamily the individual members Antibodies directed against the adhesion molecules MAC-1 or
often display overlapping chemoattractant activity. ELR-CXC ICAM-1 also reduced influx of neutrophils during experimental
chemokines, such as IL-8 and growth related protein (Gro)-a, meningitis and led to significant reductions in intracranial com-
are effective chemoattractants for neutrophils, but not for plications such as brain edema formation [51].
monocytes. In contrast, nonELR-CXC chemokines, such as Mediators of brain damage. As shown in figure 1, by fol-
IP-10 and, CC chemokines, such as monocyte chemotactic pro- lowing the steps enumerated above, activated leukocytes can
tein (MCP)-1 and MIP-1a, are poor chemoattractants for neu- release potentially tissue destructive agents including reactive
trophils but potent attractors of monocytes and lymphocytes. oxidants and proteolytic enzymes. Matrix metalloproteinases
Elevated levels of the chemokines IL-8, Gro-a, MCP-1, MIP- (MMPs) have been the focus of recent investigations, both in
1a, and MIP-1b are found in human CSF during bacterial patients with bacterial meningitis and in experimental models
meningitis [48]. Furthermore, CSF from patients with bacterial of the disease.
meningitis is chemotactic for neutrophils and mononuclear leu- MMPs. MMPS are a family of zinc-dependent endopep-
kocytes in an in vitro chemotaxis assay. Neutrophil chemotaxis tidases responsible for tissue remodeling via degradation of
is reduced by antiIL-8 and antiGro-a antibodies, and mono- extracellular matrix components [52, 53]. Collagen IV and fi-
nuclear cell migration is also reduced by a combination of bronectin are crucial components of the subendothelial basal
antiMCP-1, antiMIP-1a, and antiMIP-1b antibodies [48]. lamina of cerebral microvessels and contribute to the integrity
Brain mRNA and protein expression of MIP-2 and KC, the of the BBB. BBB disruption follows the intracerebral injection
two functional homologs of human IL-8, are markedly in- of MMPs in experimental models [54]. Although it is possible
creased during the acute phase of pneumococcal meningitis in that migrating neutrophils release MMPs to facilitate traversal
a murine model [43, 44]. Neutralization of MIP-2 bioactivity from the circulation into the subarachnoid space, evidence for
reduced neutrophil influx into the CSF in an infant rat model this process is not available. The broad-spectrum MMP inhib-
of Hib meningitis [8]. Thus, the available evidence suggests that itor BB-94 markedly attenuated BBB disruption but did not
ELR-CXC chemokines play a critical role in leukocyte traversal significantly reduce CSF pleocytosis in a rat model of menin-
into the CSF during acute bacterial meningitis. gococcal meningitis [55]. Similarly, treatment with MMP in-
Leukocyte migration into the subarachnoid space. Leuko- hibitors led to a significant reduction of CSF TNF-a concen-
cyte migration from the circulation into the extravascular space trations, BBB permeability, and the extent of neuronal injury
occurs through a multistep process governed by the sequential in an infant rat model of pneumococcal meningitis [56, 57].
activation of adhesion receptors and their ligands on both leu- MMP-9 and -8 are up-regulated in the CSF during bacterial
kocytes and the endothelium [49]. Four sequential steps (teth- meningitis in humans, and higher concentrations of MMP-9
S230 Scheld et al. JID 2002;186 (Suppl 2)

are associated with neurologic deficits in patients with disease


compared with persons who had recovered fully, suggesting
high CSF concentrations of this MMP may significantly in-
crease the risk for adverse outcome of bacterial meningitis in
humans [58].
Oxidants. In addition to proteolytic enzymes, several other
major effector molecules are available to the phagocyte that
may influence pathophysiology of meningitis including reactive
oxygen species (ROS; e.g., superoxide) and reactive nitrogen
intermediates (RNIs; e.g., NO). ROS clearly play an important
role in the pathophysiology of acute bacterial meningitis. For
example, ROS generation has been detected in brain sections
of infant rats with group B streptococcal meningitis by use of
the manganese/diamino benzidine method and in vivo in a rat
model of pneumococcal meningitis by use of the lucigenin-

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enhanced chemiluminescence technique [59, 60].
Meningitis-associated intracranial complications (including
cerebral hypoperfusion) increase intracranial pressure, brain
edema formation, and neuronal injury in experimental models
of bacterial meningitis and are attenuated or even prevented
by the use of antioxidants [61, 62]. NO/nitrite levels in the CSF
during meningitis are elevated in humans with bacterial men-
ingitis and in experimental animal models. NO production has
been observed uniformly in animal models of bacterial men-
ingitis, although administration of NOS inhibitors in experi-
mental models has yielded contradictory results ranging from
amelioration to deterioration of CNS complications and brain
damage [63, 64]. Unfortunately, NOS inhibitors are not selec-
tive for a single isoform of NOS and may have additional
pharmacologic effects unrelated to the NO pathway, thus con-
tributing to these contradictory results.
Knockout mice with a targeted disruption of single NOS
Figure 1. Mechanisms of brain damage in experimental pneumo-
coccal meningitis. NF-kB, a transcriptional activator of many genes isoforms have been useful in defining the role of NO from
involved in the pathogenesis of bacterial meningitis, encodes host fac- various enzymatic sources in the CNS [65, 66]. Mice deficient
tors including proinflammatory cytokines, chemokines (e.g., interleukin in the inducible NOS isoform exhibit significantly lower levels
[IL]-8), and adhesion molecules. The proinflammatory cytokines IL- of inflammatory mediators such as IL-1b, TNF-a, and MIP-
1b and tumor necrosis factor (TNF)-a are synthesized as inactive pre-
cursors that are processed to mature active forms by proteases (casbase
2 than wild type mice after challenge with pneumococci. Men-
1 [Casp1], also known as IL-1bconverting enzyme, and TNF-a ingitis-induced BBB disruption is significantly reduced in par-
converting enzyme [TACE]). IL-1b and TNF-a are potent activators allel [43]. When mice with the endothelial NOS knockout were
of NF-kB. This process may lead to the uncontrolled expression of used in similar experiments, aggravation of meningitis-induced
proinflammatory mediators and the increased expression of adhesion BBB permeability was observed. It appears that brain expres-
molecules both on the endothelium (e.g., intercellular adhesion mol-
ecule [ICAM]-1) and on neutrophils, leading to subsequent massive sion of proinflammatory host factors such as IL-1b, KC, MIP,
influx of leukocytes into the subarachnoid space. Once present, acti- and P-selectin may be responsible for these effects [8, 44]. It is
vated leukocytes release a complex variety of potentially cytotoxic highly likely that NO generated by separate isoforms may have
agents including oxidants and proteolytic enzymes (e.g., matrix me- different roles and potentially opposing effects during pneu-
talloproteinases [MMP]), which may contribute to tissue destruction.
mococcal meningitis. Inducible NOS seems to contribute to
Also, peroxynitrite may cause brain damage via a variety of indepen-
dent mechanisms. The best studied are attack of polyunsaturated fatty some of the harmful pathophysiologic changes of the disease
acids, leading to lipid peroxidation, and an alternative pathway that while endothelial NOS-derived NO may play a protective role,
involves oxidant-induced DNA strand breakage and subsequent poly potentially through inhibition of leukocyte endothelial inter-
(ADP ribose) polymerase (PARP) activation, which initiates an energy- actions and the production of cytokines and chemokines.
consuming intracellular cycle that ultimately results in cellular energy
depletion and cell death. Both mechanisms likely contribute to cell
Peroxynitrite is induced by various forms of inflammation
injury during pneumococcal meningitis. ECM, extracellular matrix; and ischemia/reperfusion injury and may play a central role in
MIP, macrophage inflammatory protein. bacterial meningitis from generation of oxygen and nitrogen-
JID 2002;186 (Suppl 2) Pathophysiology of Bacterial Meningitis S231

centered free radicals. Nitrotyrosine concentrations, a useful


marker for the formation of peroxynitrite, which lasts only
seconds, were elevated in the CSF of patients with acute bac-
terial meningitis when compared with noninfected controls [67].
In addition, elevated concentrations of CSF nitrotyrosine are
associated with an unfavorable clinical outcome. Nitrotyrosine
residues on proteins have been detected immunohistochemically
in leukocytes in the subarachnoid space and in other areas such
as the leptomeninges penetrating cortical and occasionally pa-
renchymal blood vessels in both adult rats with pneumococcal
meningitis and in humans [67]. Treatment with a peroxynitrite
scavenger, uric acid, significantly attenuates meningeal inflam-
mation and meningitis-associated complications. The strong
oxidant peroxynitrite is definitely a central mediator of the
pathophysiologic alterations in bacterial meningitis [8]. Figure 2. Vicious cycle of pathophysiologic alterations leading to

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neuronal injury during bacterial meningitis. BBB, blood-brain barrier;
Molecular mechanisms of oxidant-induced brain damage.
CBV, cerebral blood volume.
Peroxynitrite and other oxidants may contribute to the devel-
opment of brain damage and neuronal injury during bacterial
meningitis by a variety of mechanisms as shown in figure 1. activation may contribute substantially to endothelial cell in-
Lipid peroxidation through peroxynitrite influence on poly- jury during bacterial meningitis. Once endothelial dysfunction
unsaturated fatty acids can lead to the loss of cellular membrane occurs, the consequences include cerebrovascular autoregula-
function and integrity. Malondialdehyde and 4-hydrox-2 (E- tion loss, loss of CO2 reactivity of cerebral vessels, and increased
Nonenal 4-HNE), markers of lipid peroxidation, are found in permeability of the BBB. BBB permeability disruption allows
elevated concentrations in both patients with bacterial men- plasma constituents to enter the brain, resulting in vasogenic
ingitis and in brain homogenates of infant rats with group B cerebral edema and an increase in intracranial pressure.
streptococcal or pneumococcal meningitis [68, 69]. 4-HNE is Intracranial pressure is a multifactorial process in meningitis
found in inflammatory cells and in pial and penetrating cortical and is related not only to vasogenic edema but also cytotoxic
blood vessels by immunohistochemistry techniques. Aminoste- edema resulting from leukocyte infiltration, interstitial edema
roids, inhibitors of lipid peroxidation, attenuate the pathophy- resulting from blockade of normal CSF pathways, and in-
siologic alterations and neuronal injury in rat models of pneu- creased blood volume in the brain [74, 75]. Marked increases
mococcal meningitis [70]. Clearly, lipid peroxidation in in intracranial pressure can be deleterious in patients with bac-
meningitis is associated with brain injury. A similar staining terial meningitis by causing cerebral herniation or decreasing
pattern for 4-HNE and nitrotyrosine suggests that RNI act as cerebral perfusion (a reduction in cerebral perfusion pressure
initiators of lipid peroxidation during the disease. and/or loss of cerebrovascular autoregulation) and can ulti-
Results of experiments by a group in Munich suggest that mately lead to irreversible brain injury or death.
another alternative pathway may explain oxidant-induced dam-
age during meningitis via DNA strand breakage in subsequent
Conclusions
poly (ADP ribose) polymerase (PARP) activation that initiates
an energy-consuming intracellular cycle that ultimately results Meningitis-associated brain injury and neuronal death is not
in cellular energy depletion and cell death [71, 72]. ADP ribose mediated simply by the presence of viable bacteria but occurs
polymer formation is a well-accepted marker for PARP cata- as a consequence of the host reaction to bacterial components.
lytic activity. Poly ADP-ribosylated proteins are higher in A wide variety of inflammatory host factors involved in the
mouse and rat brains 24 h after pneumococcal inoculation than complex pathophysiologic cascade of bacterial meningitis have
in uninfected control animals [73]. Knockout mice lacking the been identified during the past decade, largely with experimen-
PARP-1 gene are protected against the development of men- tal studies, but have also been confirmed in limited studies of
ingitis-associated complications as outlined by the Munich human material. The crucial role of the caspase 1IL-1b path-
group. Inflammatory host response is reduced in parallel. Phar- way in the induction and amplification of the host inflammatory
macologic inhibition of PARP improves the clinical course of response during pneumococcal meningitis may lead to the iden-
pneumococcal meningitis. On balance, PARP activation in the tification of new potential therapeutic adjunctive agents. Sim-
brain appears to play a crucial role in the pathophysiology of ilarly, peroxynitrite and other important effector molecules con-
bacterial meningitis [8, 73]. tributing to BBB disruption and neuronal injury may be
The vicious cycle of pathophysiologic alterations. Figure 2 susceptible to adjunctive treatments.
shows that the combination of lipid peroxidation and PARP Lipid peroxidation and the activation of PARP-1 are also
S232 Scheld et al. JID 2002;186 (Suppl 2)

central mechanisms of oxidant-induced brain damage, and come related to penicillin susceptibility and dexamethasone use. Pediatrics
1998; 102:108797.
pharmacologic interference with these biochemical pathways
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