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Oral Microbiol Immunol 11: 387–394 Pediatric Infectious Diseases Revisited 199 ed. by Horst Schroten and Stefan Wirth © 2007 Birkhäuser Verlag Basel/Switzerland Role of the blood-brain barrier and blood-CSF barrier in the pathogenesis of bacterial meningitis Rüdiger Adam 1 , Kwang Sik Kim 2 and Horst Schroten 1 1 Pediatric Infectious Diseases, Klinik für Allgemeine Pädiatrie, Universitätsklinikum, Düsseldorf, Germany; 2 Pediatric Infectious Diseases, Johns Hopkins Hospital, Baltimore, Maryland, USA Abstract Despite significant progress in prevention, diagnosis and therapy acute bacterial menin- gitis remains an important cause of high morbidity and mortality in the pediatric popula- tion with no significant improvement in the outcome in recent years. Further ameliora- tion in treatment can only result from a better understanding of the pathophysiological events that occur after activation of the host’s inflammatory pathways secondary to initial bacterial invasion. The need for improved management strategies is highlighted by the observed increase in antibiotic resistance of microbial pathogens and recent develop- ments in the pharmacological treatment of meningitis patients with dexamethasone, which might adversely influence delivery of drugs to the central nervous system (CNS). In this respect the cellular and molecular events at the blood-CNS barriers come to the focus of attention. It has become evident that these anatomical and functional barriers with their differentiated functionality and vast surface area centrally contribute to the development of bacterial meningitis. This holds true not only for their role as a port of entry into the CNS but also as key players in the pathophysiological cascade following bacterial invasion into the brain. Important aspects that have to be considered are the unique anatomical and functional features of the blood-brain barrier and the blood- cerebrospinal fluid barrier, and their distinct interactions with the variety of pathogens responsible for the development of bacterial meningitis. Introduction In spite of marked progress in diagnostic procedures, improvement in intensive care and introduction of new antimicrobials, bacterial meningitis still remains a serious, sometimes life-threatening disease in children. A high number of survivors are left with persistent neurological or neuro- psychological sequelae. To improve present strategies and to develop new options in diagnostic, prevention and therapy, knowledge and understand- ing of pathogenesis and pathophysiology of bacterial meningitis is of utmost importance. It is well established that most cases of bacterial meningitis 200 Rüdiger Adam et al. develop through hematogenous spread of bacteria after crossing peripheral mucosal barriers. Even though major insights in pathophysiological events have been derived from experimental animal and in vitro models in recent years, many aspects of the subsequent invasion of the central nervous system (CNS), the role of the blood-brain barrier (BBB) and even more the blood-cerebrospi- nal fluid (CSF) barrier, remain incompletely understood. It has become clear that these anatomical and functional barriers play a central role as a port of entry into the CNS but also as key players in the pathophysiological cascade following bacterial invasion into the brain. They are involved in the often deleterious events secondary to the host immune response and are also important for therapeutic issues. Bacterial meningitis Bacterial meningitis as the most common serious infection of the CNS con- tinues to be an important cause of morbidity and mortality in children. The causative organism varies with age, immune function and immunization sta- tus. The majority of cases are associated with an infection with Streptococcus pneumoniae and Neisseria meningitidis, whereas Haemophilus influenzae type b (Hib) infections have been virtually eradicated as a result of routine vaccination policies. Streptococcus agalactiae, Escherichia coli and Listeria monocytogenes are the most common meningitis pathogens in neonates [1–3]. Bacterial meningitis typically presents with the triad of headache, fever and meningism in adolescents, but the clinical picture can vary widely in younger children [3]. Despite the development of highly effective antibi- otics, improvement of early diagnosis and intensive care management, the disease is fatal in 5–40% of the cases depending on the etiological agent and the patient’s age [2, 4]. Neurological sequelae develop in up to one third of children and adults who survive an episode of bacterial meningitis [5]. These sequelae can be related to direct damage of neuroacoustic structures with following hearing impairment, and to disturbances of CSF dynamics and cerebral blood flow with consequent hydrocephalus, brain edema and intracranial pressure. They can also be caused by direct damage of brain parenchymal tissue leading to focal sensory-motor deficits, neuropsychological impairment, or seizures [6]. Despite all improvements in early detection and antibiotic treatment, the rate of sequelae has proven to be rather unchanged in recent years [2, 7]. One main reason for this unacceptable rate of complications is the incomplete knowledge about the pathogenesis of this disease, even though experimental studies with cell cultures and animal models have substantially contributed to our understanding of the interactions of bacterial pathogens with mammalian cells and their entry into the CNS. Role of the blood-brain barrier and blood-CSF barrier… 201 The pathogenetic cascade Apart from external protection by the skull and the leptomeninges, the CNS is protected against blood-borne pathogen invasion by effective cellular barriers. Thus, a meningitis pathogen can gain access to the CNS through a defect within the external barriers, be it a congenital malformation such as a dermal sinus or a myelomeningocele, accidentally acquired or iatrogenic, e.g., after a neurosurgical procedure. An infection per continuitatem from purulent mastoiditis or sinusitis is also possible. In the vast majority of cases, however, a pathogen reaches the CNS by hematogenous seeding, after run- ning “a biological gauntlet of host defenses” [8]. It has become an accepted pathogenetic concept that the disease typically progresses through several interconnected phases of interactions between the pathogen and the host (Fig. 1). Mucosal colonization and invasion Initially, mucosal surfaces of the host’s upper respiratory and gastrointesti- nal tract are colonized by bacterial pathogens. The bacteria must attach to the mucosal epithelium and resist clearance by mechanical and immuno- logical mechanisms. All meningeal bacterial pathogens seem to express a Figure 1. Pathogenetic cascade of bacterial meningitis [9]. With friendly permission of Springer. 202 Rüdiger Adam et al. range of surface proteins that facilitates pathogen-host cell interaction. This event is followed by bacterial penetration of the mucosal epithelium either transcellularly or paracellularly, depending on the organism. Many patho- gens niftily use host-specific transport mechanisms to safely transverse this epithelial barrier. Survival within the bloodstream Once the bacteria gain access to the bloodstream, they must overcome the host defense to survive, disseminate and replicate to a sufficiently high den- sity within the blood. Several studies have suggested that a threshold level of bacteremia is necessary for a successful invasion into the CNS. To remain viable, bacterial phase variable switching of surface elements, such as the polysaccharide capsule, seems to be a prerequisite to counteract opsono- phagocytosis and complement-mediated cell lysis [10]. The population of organisms recovered from blood or CSF in the acute phase of bacteremia or meningitis is the believed to be the progeny of a few founder bacteria, often a single clone, mostly suited to survival within the bloodstream [11]. Breaching of blood-CNS barriers and replication in the CSF Reaching the blood-CNS barriers, the bacteria then attach to and transgress them through mechanisms that will be outlined in more detail below. It became evident that the host defense mechanisms within the brain are nota- bly ineffective in eliminating invading bacterial pathogens. Bacterial multi- plication within the subarachnoid space is facilitated by the virtual absence of host defensive factors such as complement and immunoglobulins, the limited number of endogenous antigen-presenting cells and the limited exchange of immune cells and mediators due to restrictive barriers [12]. As these bacterial compounds are formidable immunological stimuli, various cells within the CNS [e.g., resident leptomeningeal phagocytes, microglia, choroid plexus (CP) epithelia, endothelial cells, astrocytes] are activated to produce a wide array of proinflammatory cytokines. There is a substantial body of evidence that tumor necrosis factor-_ (TNF-_), interleukin-1` (IL- 1`) and interleukin-6 (IL-6) play a central role in this setting [13, 14]. Local intraventricular inflammation After reaching a critical bacterial concentration and subsequent stationary growth phases or after treatment with antibiotics, a number of bacterial cell wall products, toxins and DNA are released into the CSF compartment [2, 15]. In gram-positive pneumococci for example, peptidoglycans, lipoteichoic Role of the blood-brain barrier and blood-CSF barrier… 203 acid and pneumolysin are liberated after activation of autolytic hydrolases (Lyt A-C) [8]. In gram-negative infections such as meningococci, lipopoly- saccharide (LPS) and non-LPS compounds are released during growth and lysis [15, 16]. “Maximal CNS inflammation” In this critical phase of meningitis a sequence of parallel and dependent del- eterious events leads to maximal leptomeningeal inflammation. A substan- tial body of evidence mainly derived from animal and in vitro models shows that cytokines, chemokines, proteolytic enzymes, and oxidants together with an influx of leukocytes are essentially involved in the inflammatory cascade that leads to tissue destruction and brain dysfunction during bacterial men- ingitis [17] (Fig. 2). The blood-CNS barriers The homeostasis in the brain is an unconditional prerequisite for correct neu- ron function. Thus, several barrier systems are present in the brain regulating the distribution of substances between the blood stream and the CNS. Of all these CNS interfaces the BBB is not only dominant with regard to the surface area available for interchange with the CNS compartment but also with regard to coverage by scientific examinations. Neglecting other Figure 2. Concept of “maximal inflammation” [9]. With friendly permission of Springer. 204 Rüdiger Adam et al. anatomical sites of interchange, it is yet infrequently regarded as the only blood-CNS-barrier. Theoretically, blood-derived substances can gain access to the CNS access at various different anatomical sites [18]: 1. the CP with high perfusion, a wide surface area and tight barrier proper- ties despite fenestrated capillaries due to tight junctions at the epithelial lining 2. the circumventricular organs with fenestrated capillaries but a tight ependymal cell lineage of so-called tanycytes [19] 3. the ependymal lining covering the surface of intracerebral ventricles with a less tight cellular layer (gap junctions) and correspondingly less restrictions to extracellular fluid to communicate with CSF 4. the whole subarachnoid space with a network of tight capillaries in the pia mater and arachnoid mater 5. dural venous sinuses, pial and intracerebral veins or postcapillary venules Whether these barriers function as a port of entry during bacterial menin- gitis is most likely dependent on the nature of the invading microorgamism. The major barriers are described below. The blood-brain barrier The BBB is a dynamic membranous interface between the systemic cir- culation and the brain, protecting it and maintaining its homeostasis. Its anatomical base constitutes a complex system of brain microvascular endo- thelial cells (BMECs) (Fig. 3A). These cells are ensheathed by astrocytic outgrowths, which are referred to as astrocytic end-feet, necessary to main- tain barrier properties, and associated pericytes, important for structural support and vasodynamic capacity [20]. The BMECs are unique insofar as their cellular clefts are sealed by tight junctions that closely join adjacent cells, resulting in a transendothelial electrical resistance of 1000–2000 1·cm 2 [21]. Paracellular diffusion of molecules larger than M r 200–400 and the formation of extracellular fluid is thus inhibited [22]. Transcellular passage of solutes is also impeded, as the endothelial cells have only a limited pino- cytotic capacity and lack endothelial fenestrations [12]. The BBB eliminates (toxic) substances from the endothelial compart- ment and supplies the brain with nutrients and other (endogenous) com- pounds, while restricting the entrance of potentially harmful substances, e.g., bacteria and circulating toxins. It does so by specific ionic channels, transporters, energy-dependent pumps and limited receptor-mediated endocytosis [20, 23]. However, during infectious diseases of the CNS, the BBB integrity may be lost and permeability may be increased. Role of the blood-brain barrier and blood-CSF barrier… 205 The blood-CSF barrier The second system that prevents the free passage of substrates between blood and brain is the blood-CSF barrier, represented by the CP epithelium. The CP is comprised of a vascularized stromal core surrounded by epithelial cells that are aligned in villi. The CP capillaries have a much bigger diameter than cerebral microvasculature (~50 +m vs. 8 +m, respectively) [25], the per- fusion of about 5 mL/min/g is about tenfold faster than the average cerebral blood flow [24]. The cell surface is greatly increased due to an array of microvilli on the CSF side and basolateral interdigitations directed towards the basal membrane [26]. The CP surface area calculated from animal experiments is believed to be much bigger than previously appreciated, especially when put into relation to the BBB interface [27, 28]. The epithelial cells are sealed by tight junctions, which become indispensable since the endothelium of CP capillaries is fenestrated, non-continuous and has ‘window’-like openings being highly permeable to hydrophilic substrates. Thus, it is the CP epithe- lial cells welded by tight junctions that constitute the anatomical basis of the blood-CSF barrier [24] (Fig. 3B). The CPs are located throughout the fourth ventricle near the base of the brain and in the lateral ventricles inside the right and left cerebral hemisphere. They are known to be centrally involved in CSF formation and Figure 3. Parenchymal cells of the blood-brain barrier (BBB) and blood-CSF barrier. (A) Schema for the components of the BBB. The endothelial cells of the cerebral capillaries lack fenestrations and are tightly joined by zonulae occludentes (see arrows). Astrocyte foot proc- esses extensively abut the outside surface of the endothelium. The darkened area is the inter- stitial space surrounding the capillary wall (N, neuron). (B) Cross-section of a choroidal villus. A ring of choroid epithelial cells surround the interstitial fluid and adjacent vascular core. The basolateral surface of the cells has interdigitations, whereas the outer CSF-facing apical mem- brane has an extensive microvilli system. 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Dis Vet Public Health 52 : 392–3 95 Vanier G, Szczotka A, Friedl P, Lacouture S, Jacques M, Gottschalk M (2006) Haemophilus parasuis invades porcine brain microvascular endothelial cells Microbiology 152 : 1 35 142 Deli MA, Abraham CS, Kataoka Y, Niwa M (20 05) Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology Cell Mol Neurobiol 25: 59 –127 Ruffer C, Strey... microbial pathogenesis, drug delivery and neurodegenerative disorders J Neurovirol 5: 53 8 55 5 Zysk G, Schneider-Wald BK, Hwang JH, Bejo L, Kim KS, Mitchell TJ, Hakenbeck R, Heinz HP (2001) Pneumolysin is the main inducer of cytotoxicity to brain microvascular endothelial cells caused by Streptococcus pneumoniae Infect Immun 69: 8 45 852 Stins MF, Gilles F, Kim KS (1997) Selective expression of adhesion molecules... meningitidis resulted in the release of IL-6 by the endothelial cells [93] Using the same BBB model, challenge of HBMEC with S suis led, apart from secretion of chemokines, to the production of IL-6 as well [50 ] An established example of brain microvascular endothelial activation during an infectious disease is the cerebral manifestation of malaria IL-1 and TNF- are predominant cytokines released during . periodontal diseases 1 95 35 Wan AK, Seow WK, Purdie DM, Bird PS, Walsh LJ, Tudehope DI (2001) Oral colonization of Streptococcus mutans in six-month-old predentate infants. J Dent Res 80: 2060–20 65 36. chemotaxis in the Chediak-Higashi syndrome. J Clin Invest 50 : 26 45 2 652 46 Tempel TR, Kimball HR, Kakehashi S, Amen C (1972) Host factors in peri- odontal manifestations in Chediak-Higashi syndrome There is a substantial body of evidence that tumor necrosis factor-_ (TNF-_), interleukin-1` (IL- 1`) and interleukin-6 (IL-6) play a central role in this setting [13, 14]. Local intraventricular