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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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ADFP expression in human TB granulomasImmunofluorescence signals were obtained for each granuloma, and a representative image (right) and the corresponding region from an H&E stained slide (left, boxed) are shown. Nuclei are seen in blue and antigens in red.Nascent granulomas exhibit weak ADFP expression.Caseous granulomas stain strongly for ADFP.Fibrocaseous granulomas also label strongly for ADFP expression.The caseous center also has intense ADFP expression, together with nuclear debris.Resolved granulomas exhibit low levels of ADFP labeling.Control normal lung parenchyma shows ADFP expression in pneumocytes and alveolar macrophages (the left image is a merged image with bright field). Scale bar is 50 µm.
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fig03: ADFP expression in human TB granulomasImmunofluorescence signals were obtained for each granuloma, and a representative image (right) and the corresponding region from an H&E stained slide (left, boxed) are shown. Nuclei are seen in blue and antigens in red.Nascent granulomas exhibit weak ADFP expression.Caseous granulomas stain strongly for ADFP.Fibrocaseous granulomas also label strongly for ADFP expression.The caseous center also has intense ADFP expression, together with nuclear debris.Resolved granulomas exhibit low levels of ADFP labeling.Control normal lung parenchyma shows ADFP expression in pneumocytes and alveolar macrophages (the left image is a merged image with bright field). Scale bar is 50 µm.

Mentions: To investigate the localization of these proteins within the human TB granulomas, we performed immunohistological analysis on lung tissues excised from TB patients. Tissues from 32 independent Mtb-infected samples (each tissue sample had multiple granulomas) were categorized into four stages: nascent (n = 28), caseous (n = 16), fibrocaseous (n = 66) and resolved granulomas (n = 9) (Fig 2). The expression profile of the lipid droplet-associated protein, ADFP, varied markedly through the different stages of granuloma. Nascent granulomas showed weak or minimal staining (Fig 3A), whereas caseous and fibrocaseous granulomas exhibited the highest expression of ADFP (Fig 3 B and C). Interestingly, the actual caseum of several granulomas revealed strong staining for ADFP, suggesting that the lipids of the caseum were likely derived from the lipid droplets sequestered within foam cells upon the subsequent death of those cells (Fig 3D). Finally, resolved or calcified granulomas lacked detectable ADFP label (Fig 3E). Type II pneumocytes produce surfactant proteins to reduce surface tension, and the surfactant proteins are cleared or recycled by type II pneumocytes and alveolar macrophages. As a result, those cells possess lipid droplets, and ADFP was readily detected in the normal lung parenchyma (Fig 3F).


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)

ADFP expression in human TB granulomasImmunofluorescence signals were obtained for each granuloma, and a representative image (right) and the corresponding region from an H&E stained slide (left, boxed) are shown. Nuclei are seen in blue and antigens in red.Nascent granulomas exhibit weak ADFP expression.Caseous granulomas stain strongly for ADFP.Fibrocaseous granulomas also label strongly for ADFP expression.The caseous center also has intense ADFP expression, together with nuclear debris.Resolved granulomas exhibit low levels of ADFP labeling.Control normal lung parenchyma shows ADFP expression in pneumocytes and alveolar macrophages (the left image is a merged image with bright field). Scale bar is 50 µm.
© Copyright Policy
Related In: Results  -  Collection

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

fig03: ADFP expression in human TB granulomasImmunofluorescence signals were obtained for each granuloma, and a representative image (right) and the corresponding region from an H&E stained slide (left, boxed) are shown. Nuclei are seen in blue and antigens in red.Nascent granulomas exhibit weak ADFP expression.Caseous granulomas stain strongly for ADFP.Fibrocaseous granulomas also label strongly for ADFP expression.The caseous center also has intense ADFP expression, together with nuclear debris.Resolved granulomas exhibit low levels of ADFP labeling.Control normal lung parenchyma shows ADFP expression in pneumocytes and alveolar macrophages (the left image is a merged image with bright field). Scale bar is 50 µm.
Mentions: To investigate the localization of these proteins within the human TB granulomas, we performed immunohistological analysis on lung tissues excised from TB patients. Tissues from 32 independent Mtb-infected samples (each tissue sample had multiple granulomas) were categorized into four stages: nascent (n = 28), caseous (n = 16), fibrocaseous (n = 66) and resolved granulomas (n = 9) (Fig 2). The expression profile of the lipid droplet-associated protein, ADFP, varied markedly through the different stages of granuloma. Nascent granulomas showed weak or minimal staining (Fig 3A), whereas caseous and fibrocaseous granulomas exhibited the highest expression of ADFP (Fig 3 B and C). Interestingly, the actual caseum of several granulomas revealed strong staining for ADFP, suggesting that the lipids of the caseum were likely derived from the lipid droplets sequestered within foam cells upon the subsequent death of those cells (Fig 3D). Finally, resolved or calcified granulomas lacked detectable ADFP label (Fig 3E). Type II pneumocytes produce surfactant proteins to reduce surface tension, and the surfactant proteins are cleared or recycled by type II pneumocytes and alveolar macrophages. As a result, those cells possess lipid droplets, and ADFP was readily detected in the normal lung parenchyma (Fig 3F).

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