Role of the pattern recognition receptors : toll-like receptor 2 and CD14 in murine pneumococcal meningitis

Streptococcus pneumoniae is the major pathogen causing meningitis in adults. Despite antimicrobial therapy and critical care medicine, mortality remains high and about 50% of the survivors suffer from neurological sequelae. In the present study, the function of the pattern recognition receptors TLR2 and CD14 in mediating host innate immune response towards S. pneumoniae, was investigated in a mouse model of pneumococcal meningitis using mice with a targeted deletion of the corresponding genes. The role of TLR2 and CD14 are the topics of sections I and II. Modulation of outcome in wt, TLR2-/- and CD14-/- mice with meningitis by antibiotic and/or with anti-inflammatory treatment with TNF-alpha converting enzyme (TACE) inhibitor treatment is evaluated in section III.
TLR2-/- mice were found to have more severe clinical symptoms than did wt mice and subsequently showed earlier death during meningitis. This accelerated death was not due to sepsis, but rather to reduced brain bacterial clearing, followed by increased intrathecal inflammation. While the lack of TLR2 delayed bacterial clearance, leukocyte infiltration and enhanced inflammation, the lack or blockade of CD14 had no effect on bacterial clearance, but was associated with a stronger neutrophil recruitment into CSF, leading to excessive meningeal inflammation and aggravated disease after S. pneumoniae infection. In addition, this stronger neutrophil migration correlated with MIP-2 concentrations in brain and with enhanced migratory capacity of CD14-deficient PMN. In view of our observations, that different host effector functions were modulated by TLR2 and CD14 during meningitis, we asked the question whether response to therapy was also modulated by these two pattern recognition receptors. We found, that antibiotic treatment was efficient to rescue wt and CD14-/- mice, whereas in TLR2-/- strain, combination with TACE inhibitor was required. This study reveals the different effects mediated by TLR2 and CD14 respectively in meningitis and illustrates the requirement and success of adjuvant therapy, when bacterial load is high and inflammation is strong in TLR2-/- mice.