STREPTOCOCCUS PNEUMONIAE INTERACTION WITH BRAIN DERIVED GLIOBLASTOMA CELLS AND ALTERATION IN FUNCTIONAL STATE OF THE CELLS

Streptococcus pneumoniae causes meningitis with high mortality rate and survivors present long-term sequelae, including learning impairment, deafness, mental retardation and hydrocephalus. We have previously identified several bacterial adhesins and their respective receptors on epithelial and neural cells in the host, which are involved in brain development and neural cell function. We hypothesized that adhesins` mediated S. pneumoniae interaction with neural cells through the corresponding receptors may affect neural cell function and survival. Currently, we demonstrate a significant reduction in pneumococcal adhesion to the neural cells (U251, NSC-34) in the presence of the recombinant adhesins (rNOX and rGtS). Additionally, bacteria lacking the corresponding adhesins adhered significantly less efficiently to the host cells compared to the wild type (WT) bacteria. Topoisomerase I (Topo I) is an essential nuclear enzyme that participates in all DNA transaction processes and is important for gene expression. Topo I activity is significantly inhibited in S. pneumoniae-infected cells. This inhibition is significantly diminished in cells infected with null mutant bacteria in comparison to WT bacteria infected cells. In WT bacterial infected cells the reduction of Topo I activity resulted from increased ERK phosphorylation, followed by augmented ADP ribosylation of Topo I by poly ADP ribose polymerase (PARP). Inhibition of both enzymes with specific inhibitors prevented the reduction of Topo I activity in response to WT S. pneumoniae infection. Thus, in S. pneumoniae-infected neural cells Topo I activity inhibit Topo I activity via ERK phosphorylation and ADP ribosylation of Topo I by PARP. The bacteria lacking the adhesin adhere less efficiently and thus a diminished inhibition of Topo I activity in these pneumococcal-infected neural cells.