Cerebrospinal fluid transcriptional analyses reveals upregulation of IL-17, Type 1 interferon transcriptional pathways and neutrophil persistence genes associated with increased mortality from pneumococcal meningitis in adults

Abstract

Background:Improving outcomes from pneumococcal meningitis (PM), particularly in populations with high HIV prevalence, requires better understanding of host inflammatory responses to infection. Methods:We compared the transcriptome in pre-antibiotic cerebrospinal fluid (CSF) and blood from Malawian adults with PM using RNA sequencing. We used network analyses and cellular/process deconvolution of the transcriptome to identify important patho-physiological associations with outcome. Findings:Blood transcriptional profiles were obtained in 28 patients (21 HIV co-infected; median age 33 years [26-66]; median CSF WCC 28 cells/mm 3 [0-3660]; median bacterial load 4.7x10 6 copies/ml CSF [671-2x10 9 ]; in-hospital mortality 64%), paired CSF profiles were obtained in 13. Marked differences in gene expression by outcome were confined to the CSF. In non-survivors, differentially expressed genes in the CSF were co-correlated in a network of pro-inflammatory gene-clusters enriched for collagen degradation and platelet degranulation. In contrast, CSF gene expression networks from surviving patients were dominated by DNA repair, transcriptional regulation and immunological signalling. CSF expression of gene response-modules for IL-17, Type 1 interferons and IL-10 were enriched in nonsurvivors, expression of cell-specific response-modules did not differ by outcome.However, genes for neutrophil chemotaxis and persistence were highly overexpressed in non-survivors.

Pneumococcal serotype determines growth and capsule size in human cerebrospinal fluid

“…Therefore, here we studied the growth behaviour and capsule size of different serotypes in human cerebrospinal fluid (hCSF) rather than culture media to reflect more closely the environment the bacteria would encounter in a meningitis patient. Although other studies have looked at hCSF parameters in the setting of pneumococcal meningitis [24][25][26][27], data about the behaviour of S. pneumoniae in hCSF in vitro is scarce. We tested whether differences in ability to grow in hCSF in vitro and differences in capsule size correlate with serotype-specific disease severity.…”