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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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The network of genes involved in lipid metabolismGenes in blue were upregulated in caseous human pulmonary TB granulomas (Table 2), and their relationship was generated by using Ingenuity Pathway Analysis program. ADFP, ACSL1 and PSAP (SapC) are highlighted in yellow. (B) The genes in pink were either not upregulated or did not generate statistically significant values (P < 0.05).
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fig01: The network of genes involved in lipid metabolismGenes in blue were upregulated in caseous human pulmonary TB granulomas (Table 2), and their relationship was generated by using Ingenuity Pathway Analysis program. ADFP, ACSL1 and PSAP (SapC) are highlighted in yellow. (B) The genes in pink were either not upregulated or did not generate statistically significant values (P < 0.05).

Mentions: Preliminary examination of granuloma-associated abundant transcripts identified gene subsets involved in a number of destructive tissue pathologies such as invasive cancers and metabolic diseases, suggesting overlap in pathological mechanisms (Bild et al, 2006; Ma et al, 2009; Tuomisto & Yla-Herttuala, 2005). However, we focused on lipid metabolism as previous reports have documented the abundance of lipids in Mtb-infected host cells in mice and human (D'Avila et al, 2006; Hunter et al, 2007; Kondo & Kanai, 1976; Kondo & Murohashi, 1971; Kondo et al, 1970; Peyron et al, 2008; Russell et al, 2009). We noted that many of the genes encoding enzymes involved in lipid catabolism and synthesis were markedly upregulated in the transcriptome of the TB granuloma (Table 1) and generated an Ingenuity© metabolism plot that was centered around this extensive array of lipid-processing enzymes (Fig 1). The upregulated genes involved in lipid metabolism are interconnected and many of them are unified around the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α), indicating that this response is consistent with a sustained pro-inflammatory insult.


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)

The network of genes involved in lipid metabolismGenes in blue were upregulated in caseous human pulmonary TB granulomas (Table 2), and their relationship was generated by using Ingenuity Pathway Analysis program. ADFP, ACSL1 and PSAP (SapC) are highlighted in yellow. (B) The genes in pink were either not upregulated or did not generate statistically significant values (P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

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

fig01: The network of genes involved in lipid metabolismGenes in blue were upregulated in caseous human pulmonary TB granulomas (Table 2), and their relationship was generated by using Ingenuity Pathway Analysis program. ADFP, ACSL1 and PSAP (SapC) are highlighted in yellow. (B) The genes in pink were either not upregulated or did not generate statistically significant values (P < 0.05).
Mentions: Preliminary examination of granuloma-associated abundant transcripts identified gene subsets involved in a number of destructive tissue pathologies such as invasive cancers and metabolic diseases, suggesting overlap in pathological mechanisms (Bild et al, 2006; Ma et al, 2009; Tuomisto & Yla-Herttuala, 2005). However, we focused on lipid metabolism as previous reports have documented the abundance of lipids in Mtb-infected host cells in mice and human (D'Avila et al, 2006; Hunter et al, 2007; Kondo & Kanai, 1976; Kondo & Murohashi, 1971; Kondo et al, 1970; Peyron et al, 2008; Russell et al, 2009). We noted that many of the genes encoding enzymes involved in lipid catabolism and synthesis were markedly upregulated in the transcriptome of the TB granuloma (Table 1) and generated an Ingenuity© metabolism plot that was centered around this extensive array of lipid-processing enzymes (Fig 1). The upregulated genes involved in lipid metabolism are interconnected and many of them are unified around the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α), indicating that this response is consistent with a sustained pro-inflammatory insult.

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