Spatially heterogeneous lipid dysregulation in tuberculous meningitis

John Kim; Ian Spears; Clara Erice; Hye-Young H. Kim; Ned A. Porter; Caitlin Tressler; Elizabeth W. Tucker

Neurobiology of Disease (Nov 2024)

Spatially heterogeneous lipid dysregulation in tuberculous meningitis

John Kim,
Ian Spears,
Clara Erice,
Hye-Young H. Kim,
Ned A. Porter,
Caitlin Tressler,
Elizabeth W. Tucker

Affiliations

John Kim: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Ian Spears: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Clara Erice: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Hye-Young H. Kim: Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235, USA
Ned A. Porter: Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235, USA
Caitlin Tressler: Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer, Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Correspondence to: Caitlin Tressler, 720 Rutland Avenue, Room 309 Traylor Research Building, Baltimore, MD 21287, USA.
Elizabeth W. Tucker: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Correspondence to: Elizabeth W. Tucker, 1800 Orleans Street, Bloomberg Children's Center Room 6346, Baltimore, MD 21287, USA.

Journal volume & issue: Vol. 202
p. 106721

Abstract

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Tuberculous (TB) meningitis is the deadliest form of extrapulmonary TB which disproportionately affects children and immunocompromised individuals. Studies in pulmonary TB have shown that Mycobacterium tuberculosis can alter host lipid metabolism to evade the immune system. Cholesterol lowering drugs (i.e., statins) reduce the risk of infection, making them a promising host-directed therapy in pulmonary TB. However, the effect of M. tuberculosis infection on the young or adult brain lipidome has not been studied. The brain is the second-most lipid-rich organ, after adipose tissue, with a temporally and spatially heterogeneous lipidome that changes from infancy to adulthood. The young, developing brain in children may be uniquely vulnerable to alterations in lipid composition and homeostasis, as perturbations in cholesterol metabolism can cause developmental disorders leading to intellectual disabilities. To begin to understand the alterations to the brain lipidome in pediatric TB meningitis, we utilized our previously published young rabbit model of TB meningitis and applied mass spectrometry (MS) techniques to elucidate spatial differences. We used matrix assisted laser desorption/ionization-MS imaging (MALDI-MSI) and complemented it with region-specific liquid chromatography (LC)-MS/MS developed to identify and quantify sterols and oxysterols difficult to identify by MALDI-MSI. MALDI-MSI revealed several sphingolipids, glycerolipids and glycerophospholipids that were downregulated in brain lesions. LC-MS/MS revealed the downregulation of cholesterol, several sterol intermediates along the cholesterol biosynthesis pathway and enzymatically produced oxysterols as a direct result of M. tuberculosis infection. However, oxysterols produced by oxidative stress were increased in brain lesions. Together, these results demonstrate significant spatially regulated brain lipidome dysregulation in pediatric TB meningitis.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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