Intracellular location of both Nm phenotypes was confirmed finally by transmission electron microscopy (Fig. enable bacteria to survive/translocate across endothelial barriers. == Introduction == Neisseria TGR5-Receptor-Agonist meningitidis(Nm) is a human respiratory mucosal commensal and occurs asymptomatically in up to 30% of the healthy population (Cartwright, 1995). However, in susceptible individuals it can cause septicaemia and meningitis which can be life threatening. In such cases, Nm can spread rapidly from the site of colonization traversing the epithelial and endothelial barriers to reach the blood and, by the haematogenous route, disseminate to other organs TGR5-Receptor-Agonist including the brain. The rapidity of its spread may result in fatality as antibiotic therapy can be ineffective unless administered during early stages of the disease. Vaccines effective against several important disease-associated serogroups (A, C, W135, Y) are available and are based on their polysaccharide capsules. However, no effective vaccine is TGR5-Receptor-Agonist yet available against serogroup B strains currently responsible for the majority of meningococcal infections in the UK. Numerous studies have engaged in investigations on the mechanisms of pathogenesis with the aim of identifying novel vaccine antigens as well as intervention strategies which may prevent the worst outcomes of the infection. Nonetheless, a complete understanding of the molecular components of bacteria and the host that interact during infection and dissemination is yet unavailable. An important aspect of Nm pathogenesis is its ability to interact specifically with human epithelial and endothelial cells. Several major meningococcal surface structures that contribute to the successful host cell adhesion and invasion include the outer membrane proteins Opa and Opc (Virjiet al., 1992a;1993;de Vrieset al., 1998;Hardyet al., 2000;Unkmeiret al., 2002). The Opa proteins of Nm andNeisseria gonorrhoeaeand the Opc protein expressed only by Nm are beta-barrelled transmembrane molecules with four and five extracellular loops respectively. They are basic in nature and target several human receptors of which at least one class of receptors, the heparan sulfate proteoglycans, is recognized by both these proteins particularly on epithelial cells (Chenet al., 1995;de Vrieset al., 1998;Virjiet al., 1999). It is proposed that the basic residues of the proteins contained within the second loop TGR5-Receptor-Agonist (also known as HV1) of certain Opa proteins (Grantet al., 1999) or within the first two loops Rabbit Polyclonal to ZNF498 of Opc (Princeet al., 2001) may be involved in targeting proteoglycans. Notably, more recent studies suggest alternative Opc sites may be involved (Cherezovet al., 2008). However, these adhesins may also bind to other receptors which may determine tissue tropism. For example, previousin vitrostudies have shown that Opc is more effective in mediating acapsulate Nm adhesion to and invasion of endothelial cells than Opa proteins (Virjiet al., 1992b;1993). Observations on primary human umbilical vein endothelial cells (HUVECs) demonstrated that bacteria expressing high levels of Opc were highly invasive for HUVECs (Virjiet al., 1995); and while Opc also mediates invasion of epithelial cell lines of different origins (e.g. Chang, Hep-2 and A549), this occurs to a lesser extent compared with the invasion of endothelial cells (Virjiet al., 1993). Furthermore, certain meningococcal strains of the A4 cluster and the ET-37 complex that lack theopcgene can cause serious cases of meningococcal septicaemia but are less likely to cause meningitis (Sarkariet al., 1994;Seileret al., 1996), perhaps suggesting an important role of the Opc protein in crossing of the bloodcerebrospinal fluid (BCSF) barrier. This notion has been further supported by a recent study that used Opc-deficient and.