Gateways into the brain

It is still unclear why many pathogens principally have the potential to initiate meningitis, but only a relatively small number of them account for the vast majority of cases. The crucial step for all microorganisms after invasion of the host is the attachment and subsequent penetration of the structures that separate the CNS from the periphery. For most pathogens, however, the exact port of entry into the brain remains unclear.

Nonetheless, observations on cell culture and animal models as well as histological experiments allow conclusions about the primary site of invasion to be drawn. It has to be kept in mind, though, that multiple routes into the CNS compartment may be used simultaneously.

Vascular Organ Lamina Terminalis
Figure 4. Sagittal view of the anatomical relationship among the circumventricular organs (CVOs), which are located on the midline of the brain (AP, Area postrema; SFO, subfornical organ; ME, median eminence; PI, pineal gland; OVLT, organum vasculosum of the lamina terminalis) [24].

Importance of threshold bacteremia

Even though the exact sites of entry might not be exactly known, several studies suggest the probability of developing meningitis to be directly related to the concentration of bacteria in the blood and to their exceeding a critical threshold. For example, Dietzman et al. [32] reported a higher incidence of E. coli meningitis in neonates who had bacterial counts in blood > 103 CFU/mL (6 out of 11 cases, 60%) compared to those with bacterial counts less than 103 CFU/mL (1 out of 19 cases, 5%). Such associations between a certain degree of bacteremia and subsequent disease have also been described for all other pathogens relevant for meningeal infections such as Hib [33, 34], S. agalactiae [35], S. pneumoniae [36, 37], E. coli [32, 38] and, with some conflicting data, N. meningitidis [37, 39]. The infection of the CSF compartment possibly appears as a kinetic process with bacteria entering from blood and being cleared into the cerebral venous sinuses within the CSF flow. Bacteria have been shown to exit from the CSF to the venous blood through the arachnoid villi [40]. The balance of bacterial ingress and egress is proposed to be important in the establishment of meningitis and its severity [41].

The blood-brain barrier

Many investigations on meningitis pathogenesis focus on the BBB or its morphological correlate, the endothelium of the cerebral microvasculature. As outlined below, a respectable number of both in vitro and in vivo models are available. One reason for this emphasis on the BBB is its assumed preponderance regarding surface area in comparison with the other blood-CNS barriers. As one researcher puts it, "the cerebral microvasculature was chosen for morphological assessment in this study because it represents the dominant site of the BBB. The surface area of the cerebral microvas-culature is 5000-fold greater than the surface area of capillaries supplying the circumventricular organs, rendering the former more pertinent for this investigation" [42]. This view, however, has been seriously questioned by other researchers who believe the ratio to be more in the area of 1:10 taking into account more recent data derived from calculations on neonatal rat CP extrapolated to conditions in humans [27, 28]. Others have put their emphasis on the cerebral vasculature because it plays a dominant role in the pathophysiology of bacterial meningitis after the initial stages of blood-CNS barrier breakdown [43].

In an infant rat model of S. pneumoniae meningitis, brain tissue examinations from animals with positive CSF cultures revealed histopathological signs of inflammation predominantly within the meningeal region [44]. In cryostat sections of infant rat brain cortical slices, S-fimbriated E. coli strains have been shown to bind specifically to the luminal surfaces of cerebral endothelial cells besides binding to CP epithelial cells and ependymal cells [45]. In contrast, gram-negative rods were present in the subarachnoid space predominantly around the perivascular areas not in the CP, pointing towards the BBB as being the major gateway into the CSF [38].

In a mouse model, the animals that developed pneumococcal meningitis after intranasal inoculation and treatment with hyaluronidase, showed a significant inflammatory infiltrate predominantly composed of polymorpho-nuclear leukocytes preferentially around the leptomeningeal blood vessels, suggesting them to be the area of blood-CNS barrier breaching [46].

Challenge of mice with S. agalactiae by intraperitoneal injection led to bacteremia and subsequent meningitis. Histopathological studies of brain and meninges of animals with positive CSF cultures principally revealed that bacteria and leukocytic infiltrate distributed surrounding the menin-geal vessels and the perivascular spaces within the cerebral cortex [35].

Histological examination of brain tissue from a fatal case of meningococ-cal disease revealed attachment of N. meningitidis on the CP and microvas-cular endothelium, indicating that both loci may be used by meningococci for invasion of the meninges [47].

Despite decades of investigation on microbial interactions at the blood-CNS barriers, there remains a distinct paucity of studies clearly pointing towards the cerebral vasculature as the primary site of CNS invasion for certain pathogens. Probably due to this dilemma, some authors independently cite a reviewing feature in the News of the American Society of Microbiology (ASM News) [48] as the only reference for microbial BBB invasion [49-51].

However, abundant experimental studies have demonstrated that receptors for various meningeal pathogens are present on cells of cerebral capillaries potentially mediating attachment or penetration of the BBB [52, 53].

The blood-CSF barrier

For many important meningitis pathogens certain experimental data suggests the CPs to be involved in bacterial entry into the brain. Whether the blood-CSF barriers represent the primary sites of invasion or one of several ports of entry remains to be clarified. Insufficient availability of suitable in vitro models throughout recent decades may be in part responsible for the lack of supportive data.

In the fatal case of an infant having succumbed to fulminant infection with N. meningitidis, histopathological investigations of brain sections at autopsy revealed the greatest number of bacteria attaching to CP capillaries (68% in CP vs. 7% in meningeal capillaries). No meningococci were found to be adhered to the plexus epithelial cells. Interestingly the bacteria isolated from the CSF expressed significantly more PilC protein than blood isolates, suggesting this adhesin plays an important role in attachment and invasion of meningococci [47].

In Hib meningitis, early studies on infant rats suggested that invasion from the bloodstream occurred via the dural sinus veins, while other studies favored the cribriform plate or the CPs to be the main site of entry into the brain. The latter notion was supported by infant rat models with serial CSF sampling from infected animals. Here, at least in the early phases of infection before an assumed equilibrium within the CSF compartments has occurred, the highest density of bacteria was found in the CSF of the lateral ventricles in comparison to the lumbar and cortical subarachnoid space or the cisterna magna, respectively, suggesting an entry of bacteria primarily via the CPs [54].

This observation is supported by studies on primates, in which the CP has been found to be the site of earliest histopathological changes during Hib infections [55]. Another line of evidence favoring the CP to be the main site of bacterial entry is derived from the observation that, in experimental meningitis of infant primates, a concordance of bacterial density in the CSF between the lumbar subarachnoid space and the cisterna magna was observed even at low bacterial concentrations (i.e., in early stages of the disease) [56]. Since the CSF flow is unidirectionally circulating from the ventricles down to the lumbar region, the presence of bacteria in the ventricular fluid suggests entry via the CPs.

Another pathogen, Streptococcus suis, which accounts for both human and porcine meningitis cases, is also suspected of entering the CNS primarily via the blood-CSF barrier. In a porcine animal model, infected pigs were killed at the earliest clinical signs of meningitis. In these cases, in which a low bacterial density within the CSF can be assumed, streptococci were almost exclusively detected in the CP epithelium [57]. The lack of diffuse parenchymal lesions in most S. suis cases of meningitis suggests access to the CNS via the CPs.

Experiments with E. coli strains possessing S-fimbriae demonstrated specific binding sites on CP epithelial cells, to a lesser extent also to endo-thelial cells of the CP core besides vascular endothelial cells and ependymal cells. In this work, which was performed on cryostat brain sections of neonatal rats, pre-treatment of the slices with neuraminidase or a fimbrial analogue abolished attachment of E. coli, demonstrating the specificity of these interactions [45]. In contrast, in infant rats with experimental hematogenous E. coli meningitis, gram-negative rods were demonstrated around the peri-vascular area, not in the CP [38]. Thus, entry of E. coli into the CNS via the CP may be unlikely and additional studies are needed to clarify this issue.

A study on experimental listeriosis in mice showed that after subcutaneous injection the animals developed meningitis displaying a mixed inflammatory infiltration in the ventricular system, especially in the CPs. Inflammatory lesions were associated with the presence of L. monocyto-genes within phagocytic cells. It is suggested that choroiditis and meningitis developed as a consequence of hematogenous dissemination of L. monocy-togenes within mononuclear phagocytes and penetration of these cells into the ventricular system through the CP [58].

In addition, invasion of the CNS via the blood-CSF barrier may also be facilitated by the high blood flow in the CPs of up to 500 mL/g/min [24], which allows putative delivery of a relatively high number of pathogens to this site via blood stream.

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