Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism

Mi Jeong Kim, Helen C. Wainwright, Michael Locketz, Linda Gail Bekker, Gabriele B. Walther, Corneli Dittrich, Annalie Visser, Wei Wang, Fong Fu Hsu, Ursula Wiehart, Liana Tsenova, Gilla Kaplan, David G. Russell

Research output: Contribution to journalArticlepeer-review

311 Scopus citations

Abstract

The progression of human tuberculosis (TB) to active disease and transmission involves the development of a caseous granuloma that cavitates and releases infectious Mycobacterium tuberculosis bacilli. In the current study, we exploited genome-wide microarray analysis to determine that genes for lipid sequestration and metabolism were highly expressed in caseous TB granulomas. Immunohistological analysis of these granulomas confirmed the disproportionate abundance of the proteins involved in lipid metabolism in cells surrounding the caseum; namely, adipophilin, acyl-CoA synthetase long-chain family member 1 and saposin C. Biochemical analysis of the lipid species within the caseum identified cholesterol, cholesteryl esters, triacylglycerols and lactosylceramide, which implicated low-density lipoprotein-derived lipids as the most likely source. M. tuberculosis infection in vitro induced lipid droplet formation in murine and human macrophages. Furthermore, the M. tuberculosis cell wall lipid, trehalose dimycolate, induced a strong granulomatous response in mice, which was accompanied by foam cell formation. These results provide molecular and biochemical evidence that the development of the human TB granuloma to caseation correlates with pathogen-mediated dysregulation of host lipid metabolism.

Original languageEnglish
Pages (from-to)258-274
Number of pages17
JournalEMBO Molecular Medicine
Volume2
Issue number7
DOIs
StatePublished - Jul 2010

Keywords

  • Foamy macrophage
  • Granuloma
  • Mycobacterium
  • Tuberculosis

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