As stated earlier, one key factor for microbial entry into the subarachnoid space is the ability to reach a critical and sustained bacterial concentration in the bloodstream. Consequently, the ability of a pathogen to escape the host defenses is crucial for meningeal invasion.
However, high level of bacteremia per se is not sufficient for the development of meningitis. Bacterial adhesins and microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) are believed to be centrally involved in binding to blood-CNS barrier cellular receptors or interactions with extracellular matrix proteins [1, 51]. Such interactions can then promote attachment to and invasion of BMEC or CP epithelial cells, a prerequisite for bacterial penetration of the blood-CNS barriers.
In extensive studies with E. coli K1 and HBMEC, it has been shown that several microbial determinants contribute to a successful traversal of the BBB (Fig. 6).
Fimbrial proteins such as FimH or membrane proteins such as OmpA mediate attachment to the cerebral endothelium via ligand-receptor interaction and contribute to subsequent invasion [67, 135]. Other structures such as S-fimbriae, previously shown to facilitate bacterial adhesion, failed to demonstrate a pivotal role for invasion in ensuing experiments [45, 136, 137]. Components of K1 E. coli, identified as Ibe proteins, AslA, TraJ, and cytotoxic necrotizing factor 1 are believed to contribute to HBMEC invasion, even though the exact mechanisms why these E. coli determinants are required for invasion yet remain incompletely understood (summarized in ).
Several signal transduction pathways, e.g., phosphatidylinositol 3-kinase, focal adhesion kinase, Rho GTPases and others, have been shown to be involved in bacterial invasion of human BMEC, most likely through their effects on actin cytoskeleton rearrangements  (Fig. 6).
Initial attachment of S. pneumoniae involves the recognition of host cell receptor glycoconjugates . Subsequently, the bacteria invade BMEC in part via interaction between pneumococcal surface component phosphoryl-choline and the BMEC PAF receptor . This has been shown by partial inhibition of pneumococcal invasion of BMEC by a PAF receptor antagonist. Phosphorylcholine decoration was found to be up-regulated in pneu-mococci retrieved from CSF samples of experimentally infected rodents . Choline-binding protein SpsA mediates pneumococcal adherence to and invasion of mucosal epithelial cells by a human-specific interaction with the polymeric immunoglobulin receptor (pIgR)  and might be involved in crossing the blood-CSF barrier.
In addition, the PavA protein, which shows a close relationship to fibro-nectin-binding proteins of other streptococcal species, was identified as a pneumococcal adhesin for fibronectin. In an experimental mouse meningitis model, pneumococcal strains deficient in PavA showed substantially reduced adherence to and internalization of HBMEC .
Pneumolysin, a major virulence factor of S. pneumoniae, was shown to damage endothelial cells and to be an important component for compromising the BBB . Ependymal cells were shown to be damaged in a rat meningitis model by pneumolysin and hydrogen peroxide . Infection with S. pneumoniae led to a loss of ciliae, decrease in their beat frequency and damage to their ultrastructure .
Several groups had previously reported that encapsulation of N. meningitidis impedes interaction with epithelial or endothelial cells preventing their invasion or transversal . It was reasoned that relevant binding sites such as the bacterial outer membrane proteins Opa and Opc proteins were masked by the capsule . It has recently been shown in a study with mutants unable to inactivate capsule expression that fully encapsulated meningococci are well capable of adhering to HBMEC. Invasion of N. meningitidis in HBMEC was mediated by Opc binding to fibronectin, thus anchoring the bacteria to the a5p1-integrin receptor on human BMEC surface .
Invasion of N. meningitidis into HBMEC has been shown to involve c-Jun kinases 1 and 2 (JNK1 and JNK2) as their inhibition significantly reduced meningococcal invasion in HBMEC . Another factor essential for meningeal invasion by N. meningitidis seems to be an adhesin located at the tip of type IV pili, PilC. Meningeal invasion of meningococci was associated with an increase in the expression of this adhesin .
5. agalactiae (Group B streptococci)
Invasion of HBMEC by S. agalactiae was shown to require active bacterial DNA, RNA, and protein synthesis, as well as microfilament and microtu-bule elements of the eukaryotic cytoskeleton. The streptococcal polysaccha-ride capsule reduced the invasive ability of the organism . The bacteria were found inside membrane-bound vacuoles within the cells, suggesting the bacteria might induce their own uptake.
A streptococcal adhesin just recently identified for HBMEC is the fibrinogen-binding protein fbsA, which mediated attachment to the BBB but failed to support invasion of the cells . Using microarray systems and knockout bacteria a recent study determined the p-hemolysin of S. agalactiae to be the principal provocative factor for activation of HBMEC. It was found that streptococcal infection induced a highly specific and coordinate set of genes known to orchestrate neutrophil recruitment, activation and enhanced survival (e.g., CXC family chemokines IL-8, Gro-a and p, IL-
6, granulocyte-macrophage colony stimulating factor (GM-CSF), myeloid cell leukemia sequence 1 and intercellular adhesion molecule 1).
The bacterial capsule, in contrast, was believed to rather conceal the pathogen's surface to diminish host recognition. The authors concluded that the innate immune response of the BBB endothelium to S. agalactiae is to activate circulating neutrophils under modulation by specific bacterial virulence determinants .
In studies using a porcine microvascular endothelial cell line, S. suis was shown to adhere to the cells [49, 97]. In addition, intracellular survival and some degree of invasion were observed. A cytolysin was noted to be mainly responsible for endothelial damage . Besides damaging a cellular barrier with the help of suilysin, S. suis was shown to bind to porcine and human plasminogens on its surface; this could then be activated into an endogenous plasminogen activator. As acquisition of plasmin activity is a mechanism by which invasive bacteria can enhance their capabilities to destroy cell integrity this capacity may affect blood-CNS barrier permeability and contribute to the invasive potential of S. suis .
Experiments using porcine CP epithelial cells highlighted that S. suis is also able to markedly affect the barrier function and cell integrity of the
CP epithelium . Further investigations revealed that the infection with S. suis induced cell death both by apoptosis, indicated by strain-dependent DNA fragmentation and caspase activation, and by necrosis, shown by the increase of cell membrane permeability and release of nuclear high mobility group box 1 protein .
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