Cytokine response in cerebrospinal fluid of meningitis patients and outcome associated with pneumococcal serotype

Annelies Müller,Jackie Kleynhans,Alban Ramette,Anne Von Gottberg,Diana B Schramm,Susan Meiring,Linda De Gouveia,Lucy Jane Hathaway

doi:10.1038/s41598-021-99190-3

Abstract

Streptococcus pneumoniae causes life-threatening meningitis. Its capsular polysaccharide determines the serotype and influences disease severity but the mechanism is largely unknown. Due to evidence of elevated cytokines levels in the meningeal inflammatory response, we measured 41 cytokines/chemokines and growth factors in cerebrospinal fluid (CSF) samples from 57 South African meningitis patients (collected in the period 2018–2019), with confirmed S. pneumoniae serotypes, using a multiplexed bead-based immunoassay. Based on multivariable Bayesian regression, using serotype 10A as a reference and after adjusting for HIV and age, we found IL-6 concentrations significantly lower in patients infected with serotypes 6D (undetectable) and 23A (1601 pg/ml), IL-8 concentrations significantly higher in those infected with 22A (40,459 pg/ml), 7F (32,400 pg/ml) and 15B/C (6845 pg/ml), and TNFα concentration significantly higher in those infected with serotype 18A (33,097 pg/ml). Although a relatively small number of clinical samples were available for this study and 28% of samples could not be assigned to a definitive serotype, our data suggests 15B/C worthy of monitoring during surveillance as it is associated with in-hospital case fatality and not included in the 13-valent polysaccharide conjugate vaccine, PCV13. Our data provides average CSF concentrations of a range of cytokines and growth factors for 18 different serotypes (14, 19F, 3, 6A, 7F, 19A, 8, 9N, 10A, 12F, 15B/C, 22F, 16F, 23A, 31, 18A, 6D, 22A) to serve as a basis for future studies investigating host–pathogen interaction during pneumococcal meningitis. We note that differences in induction of IL-8 between serotypes may be particularly worthy of future study.

Highlights

Several studies suggest levels of cytokines such as interleukin (IL)-6, IL-8, IL-10, IL-1β and tumor necrosis factor (TNF)-α to be prognostic for the outcome of bacterial m eningitis[18] and certain pneumococcal serotypes have been associated with higher patient case-fatality ratios in large-scale epidemiological s tudies[19]
We aimed to determine the relationship between pneumococcal serotypes and (1) the inflammatory profile in residual cerebrospinal fluid (CSF) of South African patients with laboratory-confirmed pneumococcal meningitis and (2) the severity of disease to establish whether serotypes associated with a high case-fatality ratio (CFR) in a time of routine PCV vaccination, cause a distinct inflammatory reaction from the host which in turn affects the severity of disease
The analysis of cytokine concentrations indicated that CSF from meningitis patients with serotypes 6D and 23A had low levels of IL-6 whereas those with serotypes 22A, 7F and 15B/C had high levels of IL-8 and with serotype 18A had high concentrations of TNFα

Summary

Introduction

This is likely due to the challenges of assessing the large number of known circulating serotypes within one study Another reason may be the limited access to patient cerebrospinal fluid (CSF) samples to measure cytokines, to patient information and/or the difficulty of setting up experiments to analyze patient samples while considering all possible confounding factors. Despite these difficulties, an in depth understanding of the mechanisms by which pneumococcal serotypes cause differences in disease severity will be important to guide and improve future vaccine and treatment designs

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