title: A hypothetical astrocyte-microglia lactate shuttle derived from a1H NMR metabolomics analysis of cerebrospinal fluid from a cohort of South African children with tuberculous meningitis.
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.
authors.affiliation: Centre for Human Metabonomics, Faculty of Natural Sciences, North-West University (Potchefstroom Campus), Private Bag X6001, Potchefstroom, 2531 South Africa.
authors.forename: Shayne
authors.initials: S
authors.lastname: Mason
authors.affiliation: Department of Paediatric Infectious Diseases-Immunology and Rheumatology, Vrije Universiteit Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: A Marceline
authors.initials: AM
authors.lastname: van Furth
authors.affiliation: Potchefstroom Laboratory for Inborn Errors of Metabolism, Division for Biochemistry, North-West University (Potchefstroom Campus), Private Bag X6001, Potchefstroom, South Africa.
authors.forename: Lodewyk J
authors.initials: LJ
authors.lastname: Mienie
authors.affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Udo F H
authors.initials: UF
authors.lastname: Engelke
authors.affiliation: Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Tygerberg, 7505 South Africa.
authors.forename: Regan
authors.initials: R
authors.lastname: Solomons
authors.affiliation: Centre for Human Metabonomics, Faculty of Natural Sciences, North-West University (Potchefstroom Campus), Private Bag X6001, Potchefstroom, 2531 South Africa.
authors.forename: Carolus J
authors.initials: CJ
authors.lastname: Reinecke
keywords: Cerebrospinal fluid (CSF); Nuclear magnetic resonance (NMR) metabolomics; Tuberculous meningitis (TBM); “Astrocyte–microglia lactate shuttle” (AMLS) hypothesis