g. pathogen infection, protein ligands, endotoxins, and so on) and the recruited leukocyte subtypes. Given

such heterogeneity, it is difficult to make conclusion about the involvement of transcellular vs. paracellular translocation. Further, the majority of in vivo reports of transcellular translocation have been shown using methods that are often unequivocal (e.g. scanning electron microscopy, transmission electron microscopy, or confocal fluorescence microscopy); however, it is important to note when discussing such reports that some have employed single-section transmission electron microscopy only, selleck inhibitor which cannot conclusively determine the route of translocation. It is noteworthy that some pathogens may choose the easiest way for BBB translocation. Pathogens and infected leukocytes may preferentially translocate using paracellular route during in vitro experiments owing to the fact that cell–cell junctions are not well formed and developed compared to their in vivo counterparts (Hoshi & Ushiki, 1999). Moreover,

in vivo experiments may also depend on the microenvironment of the brain and BMECs that seems to be responsible for the differentiation of the BBB phenotype and astrocytic end-feet cover (Kacem et al., 1998; Rubin & Staddon, 1999; Abbott, 2002), which may influence the route of pathogen translocation. Relatively small number of pathogens is responsible for bacterial meningitis. Group B streptococci (GBS), L. monocytogenes, and S. pneumoniae account for the most cases of neonatal and early childhood bacterial meningitis (Garges et al., 2006). Streptococcus pneumoniae, Kinase Inhibitor Library supplier N. meningitidis, and H. influenzae

type b remain the most common causes of meningitis (Hart & Thomson, 2006), while meningococcus and pneumococcus cause 95% of cases of acute bacterial meningitis in children. Sporadic cases related to E. coli, M. tuberculosis, B. burgdorferi, and T. pallidum continue to be important. Fungal meningitis caused by C. neoformans, C. albicans, and Histoplasma capsulatum; and parasitic cerebral infestations caused by Acanthamoeba, Plasmodium falciparum, Trypanosoma, and Toxoplasma gondii are sporadic types of meningitis, often 3-oxoacyl-(acyl-carrier-protein) reductase observed in patients with immune deficiency. Some GBS molecules, like fibrinogen-binding protein A (Tenenbaum et al., 2005), PilA, PilB (Maisey et al., 2007), laminin-binding protein (Tenenbaum et al., 2007), beta-hemolysin/cytolysin (Doran et al., 2003), serine-rich repeat-1 (van Sorge et al., 2009), and lipoteichoic acid (LTA) (Doran et al., 2005), mediate interaction of the pathogen with BMECs and penetration of the BBB. Many of these GBS ligands are known to bind ECM molecules such as fibronectin, fibrinogen, and laminin, which successively bind host-cell-surface proteins such as integrins. GBS ligands and their receptors on BMECs described earlier are depicted in Table 1.