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Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism.

Kim MJ, Wainwright HC, Locketz M, Bekker LG, Walther GB, Dittrich C, Visser A, Wang W, Hsu FF, Wiehart U, Tsenova L, Kaplan G, Russell DG - EMBO Mol Med (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

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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SapC expression in human TB granulomasImmunofluorescence signals were obtained for each granuloma, and a representative image (right) and the corresponding area from an H&E stained slide (left, boxed) are shown. Nuclei are seen in blue and antigens in red.A, B, C. SapC is expressed in nascent granuloma (A), caseous granulomas (B), and fibrocaseous granulomas (C).D. Resolved granulomas show weak expression. Scale bar is 50 µm.
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fig05: SapC expression in human TB granulomasImmunofluorescence signals were obtained for each granuloma, and a representative image (right) and the corresponding area from an H&E stained slide (left, boxed) are shown. Nuclei are seen in blue and antigens in red.A, B, C. SapC is expressed in nascent granuloma (A), caseous granulomas (B), and fibrocaseous granulomas (C).D. Resolved granulomas show weak expression. Scale bar is 50 µm.

Mentions: The expression pattern of ACSL1 was found to be very similar to that of ADFP. Nascent granulomas had almost no staining, while MGCs occasionally showed very weak staining (Fig 4A). In contrast, the cellular regions subtending the capsules of caseous and fibrocaseous granulomas were robustly stained with the ACSL1 antibody (Fig 4B and C). Similarly to ADFP, resolved granulomas showed no ACSL1 expression, with the exception of a few cells (Fig 4D). ACSL1 is important for normal cell functions; thereby it was detectable in normal lung parenchyma (Fig 4E). SapC expression differed slightly from ADFP and ACSL1 in that it was strongly expressed in macrophages and MGCs even in nascent granulomas (Fig 5A). In caseous and fibrocaseous granulomas, SapC was expressed along the capsule that contained many macrophages and MGCs (Fig 5B and C). Similarly to ADFP and ACSL1, SapC expression was very weak or not detected in resolved granulomas (Fig 5D). There was no detectable level of SapC expression in normal lung parenchyma (data not shown).


Caseation of human tuberculosis granulomas correlates with elevated host lipid metabolism.

Kim MJ, Wainwright HC, Locketz M, Bekker LG, Walther GB, Dittrich C, Visser A, Wang W, Hsu FF, Wiehart U, Tsenova L, Kaplan G, Russell DG - EMBO Mol Med (2010)

SapC expression in human TB granulomasImmunofluorescence signals were obtained for each granuloma, and a representative image (right) and the corresponding area from an H&E stained slide (left, boxed) are shown. Nuclei are seen in blue and antigens in red.A, B, C. SapC is expressed in nascent granuloma (A), caseous granulomas (B), and fibrocaseous granulomas (C).D. Resolved granulomas show weak expression. Scale bar is 50 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2913288&req=5

fig05: SapC expression in human TB granulomasImmunofluorescence signals were obtained for each granuloma, and a representative image (right) and the corresponding area from an H&E stained slide (left, boxed) are shown. Nuclei are seen in blue and antigens in red.A, B, C. SapC is expressed in nascent granuloma (A), caseous granulomas (B), and fibrocaseous granulomas (C).D. Resolved granulomas show weak expression. Scale bar is 50 µm.
Mentions: The expression pattern of ACSL1 was found to be very similar to that of ADFP. Nascent granulomas had almost no staining, while MGCs occasionally showed very weak staining (Fig 4A). In contrast, the cellular regions subtending the capsules of caseous and fibrocaseous granulomas were robustly stained with the ACSL1 antibody (Fig 4B and C). Similarly to ADFP, resolved granulomas showed no ACSL1 expression, with the exception of a few cells (Fig 4D). ACSL1 is important for normal cell functions; thereby it was detectable in normal lung parenchyma (Fig 4E). SapC expression differed slightly from ADFP and ACSL1 in that it was strongly expressed in macrophages and MGCs even in nascent granulomas (Fig 5A). In caseous and fibrocaseous granulomas, SapC was expressed along the capsule that contained many macrophages and MGCs (Fig 5B and C). Similarly to ADFP and ACSL1, SapC expression was very weak or not detected in resolved granulomas (Fig 5D). There was no detectable level of SapC expression in normal lung parenchyma (data not shown).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

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.

Show MeSH
Related in: MedlinePlus