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Cited by 489Tuberculosis Research and EpidemiologyLipid metabolism and biosynthesisImmune responses and vaccinations

Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism

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Kim, Mi‐Jeong, Wainwright, Helen C., Locketz, Michael, Bekker, Linda‐Gail, Walther, Gabriele B., Dittrich, Corneli, Visser, Annalie, Wang, Wei +5 more·2010·EMBO Molecular Medicine
DOI 10.1002/emmm.201000079PMC PMC2913288
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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.

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Authors
Kim, M., Wainwright, H. C., Locketz, M., Bekker, L., Walther, G. B., Dittrich, C., Visser, A., Wang, W., Hsu, F., Wiehart, U., Tsenova, L., Kaplan, G., & Russell, D. G.
Affiliations
  • Cornell University (US)
  • University of Cape Town (ZA)
  • Washington University in St. Louis (US)
Corresponding author
Russell, David G.
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2010-07-01
Volume
2
Issue
7
Pages
258-274
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.1002/emmm.201000079
PMC
PMC2913288
OpenAlex
W2151390802
Cited by
489
References
3
Citations by year
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FWCI
13.27
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL 055936, R01HL055936)
  • National Institute of Allergy and Infectious Diseases (AI054338, R01AI054338)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
tuberculosis, caseous granuloma, host lipid metabolism, adipophilin, ACAT1, saposin C, lipid droplets, macrophages, trehalose dimycolate, granulomatous inflammation, foam cells, Mycobacterium tuberculosis, cholesterol, cholesterol esters, triglycerides, lactosylceramide
MeSH terms
Perilipin-2, Long-Chain-Fatty-Acid-CoA Ligase, Animals, Caseins, Cholesterol, Cholesterol Esters, Coenzyme A Ligases, Cord Factors, Granuloma, Humans, Lactosylceramides, Lung Diseases, Macrophages, Membrane Proteins, Necrosis, Peptides, Triglycerides, Tuberculosis, Antigens, CD, Saposins, Lipid Metabolism, Mice, Gene Regulatory Networks

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