A hypothetical astrocyte-microglia lactate shuttle derived from a 1H NMR metabolomics analysis of cerebrospinal fluid from a cohort of South African children with tuberculous meningitis.

Shayne Mason,A Marceline Van Furth,Regan Solomons,Ron A Wevers,Udo F H Engelke,Carolus J Reinecke,Lodewyk J Mienie

doi:10.1007/s11306-014-0741-z

Abstract

Tuberculosis meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis and is particularly intense in small children; there is no universally accepted algorithm for the diagnosis and substantiation of TB infection, which can lead to delayed intervention, a high risk factor for morbidity and mortality. In this study a proton magnetic resonance (1H NMR)-based metabolomics analysis and several chemometric methods were applied to data generated from lumber cerebrospinal fluid (CSF) samples from three experimental groups: (1) South African infants and children with confirmed TBM, (2) non-meningitis South African infants and children as controls, and (3) neurological controls from the Netherlands. A total of 16 NMR-derived CSF metabolites were identified, which clearly differentiated between the controls and TBM cases under investigation. The defining metabolites were the combination of perturbed glucose and highly elevated lactate, common to some other neurological disorders. The remaining 14 metabolites of the host’s response to TBM were likewise mainly energy-associated indicators. We subsequently generated a hypothesis expressed as an “astrocyte–microglia lactate shuttle” (AMLS) based on the host’s response, which emerged from the NMR-metabolomics information. Activation of microglia, as implied by the AMLS hypothesis, does not, however, present a uniform process and involves intricate interactions and feedback loops between the microglia, astrocytes and neurons that hamper attempts to construct basic and linear cascades of cause and effect; TBM involves a complex integration of the responses from the various cell types present within the CNS, with microglia and the astrocytes as main players.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-014-0741-z) contains supplementary material, which is available to authorized users.

Highlights

Tuberculosis (TB), one of the major contemporary pandemics, is caused by Mycobacterium tuberculosis (Mtb); its worldwide impact remains a serious concern
This section of the spectrum serves to illustrate some of the discernible qualitative Nuclear magnetic resonance (NMR) differences associated with the cerebrospinal fluid (CSF) taken from the TBMinfected infants and small children compared to non-Tuberculosis meningitis (TBM) cases
Unsupervised principal component analysis (PCA) of all 3 experimental groups separated the TBM cases and both control groups, with some overlap between the control groups indicating that they shared similar characteristics but were not homogeneous

Summary

Introduction

Tuberculosis (TB), one of the major contemporary pandemics, is caused by Mycobacterium tuberculosis (Mtb); its worldwide impact remains a serious concern. The disease in children is severe as diagnosis is difficult since its identification in children usually results from a combination of, often asymptomatic, clinical criteria, non-specific TB tests and diagnostic markers, all of which have a low sensitivity and specificity (van Well et al 2009), leading to delayed intervention, and a high risk of morbidity and mortality. Central nervous system (CNS) TB accounts for an estimated 1–10 % of all EPTB (Cherian and Thomas 2011; Bhigjee et al 2007; Rock et al 2005), with tuberculous meningitis— known as TB meningitis (TBM)— being the most severe complication of the disease and the most common form of bacterial meningitis (BM) in South African children (Wolzak et al 2012). Most TBM patients upon admission present with an advanced stage of disease due to difficulty of diagnosis in the early stages, resulting in an estimated 30 % of patients dying despite treatment (Youssef et al 2006)

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