Guerra-Assuncao, J.-A.; Chakroborty, P.; Pollara, G.; Venturini, C.; Mlozowa, V. S.; Denis, B.; Nyirenda, M.; Lalloo, D. G.; Noursadeghi, M.; Heyderman, R. S.; Brown, J. S.; Wall, E. C.

Background: Pneumococcal meningitis (PM) has persistently poor clinical outcomes, especially in sub-Saharan Africa. To better characterise the inflammatory response and identify factors associated with mortality we compared paired peripheral blood and cerebrospinal fluid (CSF) transcriptomes before the initiation of antibiotics in Malawian adults with proven PM. Results: Blood transcriptional profiles were obtained in 28 patients with PM, with simultaneous paired with CSF profiles available for 13 patients. 15/28 (52%) patients died. Comparison of the transcriptome between CSF and blood compartments showed upregulation of 2293 differentially expressed genes in CSF and 909 in blood; enriched pathways in CSF included inflammasome activity and neutrophil migration/activation in the CSF, contrasting with enrichment for pathways including platelet and endothelial activation, cell cycle, cytokine release and oxidative stress in the blood transcriptome. Comparison of CSF profiles between survivors and non-survivors revealed 1829 differentially expressed genes, non-survivor CSF was enriched for multiple innate inflammatory pathways, including IL-17A and Type 1 interferons and proteolysis. In contrast, minimal transcriptomic differences between outcome groups were detected in blood. Conclusion: Inflammation in PM is characterised by compartmentalised responses in blood and CSF. Poorer outcomes are associated with an dysregulated innate immune host response to S. pneumoniae in the CSF compartment.