Transcriptomics of toll like receptor signaling pathway in children with acute bacterial meningitis

Abstract

Background : The invading bacterial pathogens are recognized by a class of pathogen recognition receptors (PRRs) called Toll Like receptors (TLRs) present on immune cells. PRRs play an important role in elimination of pathogens in early part of the disease but also results in unabated inflammation. There is a sparse literature on TLR transcriptome and their role in mediating immune response in bacterial meningitis. Methods : Children hospitalized with bacterial meningitis (ABM, n=30) and aseptic meningitis (ASM, n=11) were enrolled. Controls (n=15) included the children, where CSF tap didn’t yield any infection on lab investigation. The gene expression profile of forty-two genes of TLR signaling pathway was performed using PCR array platform. Further, these results were validated by estimating secretory cytokines and chemokines in CSF using Luminex platform and western blotting. Results : We observed an increased expression of TLR2 (2 folds),TLR3 (13 folds), TLR8 (3 folds), TLR9 (20 folds), CD180(8 folds), TICAM1 and TIRAP dependent signaling pathway genes including of TNF? (8 folds), IL6 (114 folds), IL12 (64 folds), IL10 (17 folds), CCL4 (18 folds), CCL5 (7 folds) and CXCL8 (31 folds) in children with ABM. The protein expression of TLR signaling genes (TLR3,TNF?,IL-1ÃY, IL-6,IL-8, IL10,IL1ra) was observed to increase in children with ABM in comparison with ASM and controls. Further, we also observed higher CSF levels of IL-1ÃY, IL-6, IL-17, IL1ra, IL-8, MCP-1 & RANTES in children with ABM as compared to ASM and controls. Conclusion : An overall upregulation of TLRs and downstream TLR signaling molecules was observed. This subsequently resulted in increased levels of inflammatory cytokines and chemokines in children with ABM. The study provides an insight to role of TLR signaling in augmentation of immune response in pediatric bacterial meningitis which can be further explored for therapeutic intervention to regulate unabated inflammatory process in bacterial meningitis.