Role of Connexins and Ca2+ signaling during pneumococcal meningitis – CALPLYCX

Streptococcus pneumoniae(PN) is a human nasopharyngeal commensal and major aetiological agent of bacterial meningitis. Our preliminary results indicate that cytotoxicity linked to PN and its major virulence factor pneumolysin (Ply) implicates calcium (Ca2+) signalling mediated by connexins (Cxs), the components of intercellular Gap junctions. Mice infection studies indicate that expression of astroglial Cx43 favoured PN translocation in the brain and meningitis. We also found that Ply-independent secreted factors (PSFs) associated with PN strains causing meningitis trigger Ca2+ signalling and endothelial cell cytotoxicity. The goal of this proposal is to identify and characterize these PSFs, as well as their role and that of Ply in Cxs- and Ca2+-mediated signalling during bacterial crossing of the Blood Brain Barrier (BBB) using a unique reconstituted in vitro model. The role of PSFs in the crossing of the BBB will be characterized in a mice model of PN meningitis.