Deciphering the TLR transcriptome and downstream signaling pathway in cerebrospinal fluid in pediatric meningitis.

Objective/design: Pediatric meningitis is characterized by a colossal inflammatory response to the pathogen in the central nervous system (CNS). This unabated inflammatory response persists even after the removal of the pathogen by antibiotics/steroids causing collateral damage to CNS tissue. Toll-like receptors (TLRs) are the key players in the recognition and elicitation of innate-immune response against bacterial/viral components in cerebrospinal fluid (CSF). Till date, the precise understanding of TLR-triggered inflammatory response in pediatric meningitis is lacking. The present study was designed to delineate the role of TLR transcriptome and downstream signaling pathways in CSF of pediatric meningitis. Methods: Children in the age group of > 3 months to 12 years with pediatric meningitis were included. A total of 249 cases of pediatric meningitis (bacterial = 89, viral = 160) were included. In addition, 71 children who tested negative to the pathogen in CSF tap and did not have signs of infection clinically constituted the controls. RNA was extracted from the CSF samples of both cases and controls. The relative gene expression profile of 42 TLR signaling pathway genes was performed. For the analysis of secretory cytokines and chemokines in CSF, Luminex assay was performed. Results: We report global upregulation of TLR genes in patients with acute bacterial meningitis (ABM). The downstream signaling molecules were upregulated as well. The CSF of pediatric ABM patients revealed a predominant pro-inflammatory milieu marked by increased levels of pro-inflammatory cytokines. A significant correlation between poor clinical outcomes of patients and an increased expression of TLR/pro-inflammatory cytokine genes was observed. Conclusion: Our findings provide support for future studies exploring TLR-based adjunct therapy to limit the neurological sequelae, owing to persistent inflammation in pediatric ABM patients. [ABSTRACT FROM AUTHOR]