• Open Access

Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism

Authors

  • Mi-Jeong Kim,

    1. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
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  • Helen C. Wainwright,

    1. Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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  • Michael Locketz,

    1. Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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  • Linda-Gail Bekker,

    1. Department of Medicine, The Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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  • Gabriele B. Walther,

    1. Chris Barnard Division of Cardio-Thoracic Surgery, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa
    Current affiliation:
    1. Department for General, Abdominal, Vascular and Thoracic Surgery, Klinikum Bogenhausen, Teaching Hospital of the TU München, Munich, Germany.
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  • Corneli Dittrich,

    1. Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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  • Annalie Visser,

    1. Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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  • Wei Wang,

    1. Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
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  • Fong-Fu Hsu,

    1. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
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  • Ursula Wiehart,

    1. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
    Current affiliation:
    1. Medical Biosciences Department, University of the Western Cape Bellville, South Africa.
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  • Liana Tsenova,

    1. Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center at UMDNJ, Newark, NJ, USA
    Current affiliation:
    1. Medical Biosciences Department, University of the Western Cape Bellville, South Africa.
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  • Gilla Kaplan,

    1. Laboratory of Mycobacterial Immunity and Pathogenesis, Public Health Research Institute Center at UMDNJ, Newark, NJ, USA
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  • David G. Russell

    Corresponding author
    1. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
    • Tel: +1 607 253 4272; Fax: +1 607 253 4058

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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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