Microbial translocation across the bloodCNS barrier

Recent studies on E. coli have elegantly shown that successful crossing of the BBB by circulating bacteria requires, as mentioned above, a certain degree of bacteremia, a direct attachment of the microbe to and subsequent invasion of the endothelial cells, a rearrangement of the BMEC actin cyto-skeleton and the traversal of the cells alive [1, 53, 115].

Once attachment to the tight blood-CNS barriers has occurred, several pathogen-specific strategies can be employed to migrate across and gain access to the CSF space (Fig. 5):

- disruption of tight cell-to-cell contacts and passage between the cells (paracellular route)

- direct or indirect invasion of the endothelial cells, permeation and release in a vital state on the contralateral side of the barrier (transcellular passage)

Figure 5. Possible strategies of microbial penetration of blood-CNS barriers [9]. With friendly permission of Springer.

- penetration of the barrier attached to or phagocytosed by leukocytes during their diapedesis (direct or 'modified' Trojan horse mechanism)

- destruction of the barrier by cellular injury, e.g., due to release of cytotoxic enzymes or bacterial fragments.

Transcellular passage

Just like overcoming the nasopharyngeal barriers, pathogens use several host transport systems to breach the blood-CNS barrier. For N. meningiti-dis, interaction between surface proteins (Opc) with endothelial integrin receptors is important [116]. S. pneumoniae utilizes the internalization of platelet-activation factor (PAF) receptor via binding of phosphorylcholine and is likewise incorporated. While a fraction of the internalized pneumo-cocci dies, others transverse the cells via transcytosis [117]. A similar mode of action is known for S. agalactiae. They are also internalized by "induced transcytosis" after attachment to fibrinogen, even though in higher densities they might also damage the cellular barrier by release of toxins (see also below) [52, 118, 119].

E. coli displays attachment and invasion characteristics specific for cerebral endothelial cells. They adhere to and invade HBMEC using several capsular and fimbrial epitopes and can be found within intracellular vacuoles of HBMEC [67]. Bacterial proteins necessary for bacterial invasion have been identified, i.e., IbeA, IbeB, YijP and CNF1 [52, 65, 67]. Using the host cytoskeleton they are able to transverse the BBB and reach the CNS in a vital state.

Other pathogens believed to breach the BBB by transcellular passage are L. monocytogenes [120], Mycobacterium tuberculosis [121], and fungal pathogens such as Candida albicans [122] and Cryptococcus neoformans [123]. Figure 5 illustrates possible strategies of microbial penetration of blood-CNS barriers [9].

Paracellular/intercellular passage

If cerebral endothelial cells are confronted with high bacterial loads, other factors besides the transcellular passage supposedly become relevant. Both the p-hemolysin production of S. agalactiae and the pneumolysin of S. pneumoniae are capable of damaging the endothelial layer integrity, thus possibly allowing direct paracellular passage of bacteria [52, 124]. In studies on Hib, it has been suspected that the bacteria cross the BBB paracellularly [125]. Borrelia burgdorferi is also suspected of reaching the subarachnoid space after paracellular penetration, although some aspects point at a trans-cellular route as well [126]. Protozoans such as Trypanosoma brucei at least partly penetrate endothelial linings via a paracellular mechanism, although recently transcellular permeation has been documented [127].

Transmigration via leucocytes (Trojan horse mechanism)

Pathogens with the ability to survive within phagocytes can take advantage of being phagocytosed and reach the brain when their "Trojan horses" migrate through blood-CNS barriers. Such mechanisms have been suggested for Brucella spp., M. tuberculosis and L. monocytogenes [128, 129]. It is of interest that, in some events, Listeria are even able to spread by retrograde neuronal transport from the periphery to the CNS [130]. Whether this intra-axonal movement is pathogenetically relevant in humans is not known yet.

Intracellular survival in macrophages has also been demonstrated for S. agalactiae [131] and E. coli [132], but it is unclear whether this property has any relevance to transversal of blood-CNS barriers. In S. suis, a "modified Trojan horse" mechanism, in which bacteria transverse blood-CNS barriers by adhering to diapeding macrophages, rather than residing in phagosomes within them, was discussed [133, 134].

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