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Lipid cholesterol metabolism mycobacterium tuberculosis

Areej Abuhammad
Tuberculosis (TB), although a curable disease, is still one of the most difficult infections to treat. Mycobacterium tuberculosis infects 10 million people worldwide and kills 1.5 million people each year. Reactivation of a latent infection is the major cause of TB. Cholesterol is a critical carbon source during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into lipid virulence factors. The M. tuberculosis genome contains a large regulon of cholesterol catabolic genes suggesting that the microorganism can utilize host sterol for infection and persistence...
July 2017: British Journal of Pharmacology
Yaroslav Faletrov, Anna Brzostek, Renata Plocinska, Jarosław Dziadek, Elena Rudaya, Irina Edimecheva, Vladimir Shkumatov
Fluorescent steroids BODIPY-cholesterol (BPCh) and 7-nitrobenzoxadiazole-4-amino-(NBD)-labeled 22-NBD-chelesterol (22NC) as well as synthesized 20-(NBD)-pregn-5-en-3β-ol (20NP) were found to undergo bioconversions by Mycobacterium tuberculosis H37Rv and M. smegmatis mc(2) 155. The major fluorescent products were determined to be 4-en-3-one derivatives of the compounds. Degradation of NBD fluorophore was also detected in the cases of 22NC and 20NP, but neither NBD degradation nor steroidal part modification were observed for the synthesized 3-(NBD)-cholestane...
January 2017: Steroids
Saikou Y Bah, Paul Dickinson, Thorsten Forster, Beate Kampmann, Peter Ghazal
Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signalling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signalling to regulate the dynamics of cholesterol synthesis and homeostasis...
May 2017: Journal of Steroid Biochemistry and Molecular Biology
Rustin R Lovewell, Christopher M Sassetti, Brian C VanderVen
The interplay between Mycobacterium tuberculosis lipid metabolism, the immune response and lipid homeostasis in the host creates a complex and dynamic pathogen-host interaction. Advances in imaging and metabolic analysis techniques indicate that M. tuberculosis preferentially associates with foamy cells and employs multiple physiological systems to utilize exogenously derived fatty-acids and cholesterol. Moreover, novel insights into specific host pathways that control lipid accumulation during infection, such as the PPARγ and LXR transcriptional regulators, have begun to reveal mechanisms by which host immunity alters the bacterial micro-environment...
February 2016: Current Opinion in Microbiology
Maria Angela M Marques, Marcia Berrêdo-Pinho, Thabatta L S A Rosa, Venugopal Pujari, Robertha M R Lemes, Leticia M S Lery, Carlos Adriano M Silva, Ana Carolina R Guimarães, Georgia C Atella, William H Wheat, Patrick J Brennan, Dean C Crick, John T Belisle, Maria Cristina V Pessolani
UNLABELLED: Mycobacterium leprae induces the formation of lipid droplets, which are recruited to pathogen-containing phagosomes in infected macrophages and Schwann cells. Cholesterol is among the lipids with increased abundance in M. leprae-infected cells, and intracellular survival relies on cholesterol accumulation. The present study investigated the capacity of M. leprae to acquire and metabolize cholesterol. In silico analyses showed that oxidation of cholesterol to cholest-4-en-3-one (cholestenone), the first step of cholesterol degradation catalyzed by the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD), is apparently the only portion of the cholesterol catabolic pathway seen in Mycobacterium tuberculosis preserved by M...
December 2015: Journal of Bacteriology
Tom A Mendum, Huihai Wu, Andrzej M Kierzek, Graham R Stewart
BACKGROUND: Mycobacterium tuberculosis continues to kill more people than any other bacterium. Although its archetypal host cell is the macrophage, it also enters, and survives within, dendritic cells (DCs). By modulating the behaviour of the DC, M. tuberculosis is able to manipulate the host's immune response and establish an infection. To identify the M. tuberculosis genes required for survival within DCs we infected primary human DCs with an M. tuberculosis transposon library and identified mutations with a reduced ability to survive...
May 9, 2015: BMC Genomics
Jacob J Baker, Benjamin K Johnson, Robert B Abramovitch
During pathogenesis, Mycobacterium tuberculosis (Mtb) colonizes environments, such as the macrophage or necrotic granuloma, that are acidic and rich in cholesterol and fatty acids. The goal of this study was to examine how acidic pH and available carbon sources interact to regulate Mtb physiology. Here we report that Mtb growth at acidic pH requires host-associated carbon sources that function at the intersection of glycolysis and the TCA cycle, such as pyruvate, acetate, oxaloacetate and cholesterol. In contrast, in other tested carbon sources, Mtb fully arrests its growth at acidic pH and establishes a state of non-replicating persistence...
October 2014: Molecular Microbiology
Yun Lu, Feng Qiao, Xue-Fu You, Xin-Yi Yang
Identification and validation of a new target is one of the most important steps for new antituberculosis (TB) drug discovery. Researches have shown that Mycobacterium tuberculosis (Mtb) encodes 20 CYP450 enzymes which play important roles in the synthesis and metabolism of lipid, cholesterol utilization, and the electron transport of respiratory chain in Mtb. With the critical roles within the organism as well as the protein structures of six Mtb CYP450 enzymes being clarified, some of them have been highlighted as potential anti-tuberculosis targets...
April 2014: Yao Xue Xue Bao, Acta Pharmaceutica Sinica
Irène Caire-Brändli, Alexia Papadopoulos, Wladimir Malaga, David Marais, Stéphane Canaan, Lutz Thilo, Chantal de Chastellier
During the dormant phase of tuberculosis, Mycobacterium tuberculosis persists in lung granulomas by residing in foamy macrophages (FM) that contain abundant lipid bodies (LB) in their cytoplasm, allowing bacilli to accumulate lipids as intracytoplasmic lipid inclusions (ILI). An experimental model of FM is presented where bone marrow-derived mouse macrophages are infected with M. avium and exposed to very-low-density lipoprotein (VLDL) as a lipid source. Quantitative analysis of detailed electron microscope observations showed the following results...
February 2014: Infection and Immunity
Jin Gao, Nicole S Sampson
The Mycobacterium tuberculosis Rv3409c gene is required for modulation of the Toll-like receptor 2 (TLR-2) signaling response in infected macrophages. Although each is annotated as encoding a cholesterol oxidase, neither Rv3409c nor its ortholog MSMEG1604 is required for the metabolism of cholesterol in mycobacteria. Here we report that a unique lipid, L1334, accumulates in a MSMEG1604 transposon mutant in the Mycobacterium smegmatis cell envelope. L1334 is a polar glycopeptidolipid that is hyperrhamnosylated and in which the 6-deoxytalose moiety is not acetylated...
February 4, 2014: Biochemistry
Irène Caire-Brändli, Alexia Papadopoulos, Wladimir Malaga, David Marais, Stéphane Canaan, Lutz Thilo, Chantal de Chastellier
During the dormant phase of tuberculosis, Mycobacterium tuberculosis persists in lung granulomas by residing in foamy macrophages (FM) that contain abundant lipid bodies (LB) in their cytoplasm, allowing bacilli to accumulate lipids as intra-cytoplasmic lipid inclusions (ILI). An experimental model of FM is presented where bone marrow-derived mouse macrophages are infected with M. avium and exposed to very low density lipoprotein (VLDL) as a lipid source. Quantitative analysis of detailed electron microscope observations showed the following results: (i) Macrophages became foamy and mycobacteria formed ILI, for which host triacylglycerides, rather than cholesterol, was essential; (ii) Lipid transfer occurred via mycobacteria-induced fusion between LB and phagosomes; (iii) Mycobacteria showed a thinned cell wall and became elongated; (iv) Upon removal of VLDL, LB and ILI declined within hours and simultaneous resumption of mycobacterial division restored the number of mycobacteria to the same level as that found in untreated control macrophages...
November 25, 2013: Infection and Immunity
Wonsik Lee, Brian C VanderVen, Ruth J Fahey, David G Russell
Recent data indicate that the nutrients available to Mycobacterium tuberculosis (Mtb) inside its host cell are restricted in their diversity. Fatty acids and cholesterol appear more favored; however, their degradation can result in certain metabolic stresses. Their breakdown can generate propionyl-CoA, which gives rise to potentially toxic intermediates. Detoxification of propionyl-CoA relies on the activity of the methylcitrate cycle, the methylmalonyl pathway, or incorporation of the propionyl-CoA into methyl-branched lipids in the cell wall...
March 8, 2013: Journal of Biological Chemistry
Suzanne T Thomas, Brian C VanderVen, David R Sherman, David G Russell, Nicole S Sampson
Mycobacterium tuberculosis, the bacterium that causes tuberculosis, imports and metabolizes host cholesterol during infection. This ability is important in the chronic phase of infection. Here we investigate the role of the intracellular growth operon (igr), which has previously been identified as having a cholesterol-sensitive phenotype in vitro and which is important for intracellular growth of the mycobacteria. We have employed isotopically labeled low density lipoproteins containing either [1,7,15,22,26-(14)C]cholesterol or [1,7,15,22,26-(13)C]cholesterol and high resolution LC/MS as tools to profile the cholesterol-derived metabolome of an igr operon-disrupted mutant (Δigr) of M...
December 23, 2011: Journal of Biological Chemistry
Kevin W Bruhn, Chaitra Marathe, Ana Cláudia Maretti-Mira, Hong Nguyen, Jacquelyn Haskell, Thu Anh Tran, Veena Vanchinathan, Upasna Gaur, Mary E Wilson, Peter Tontonoz, Noah Craft
BACKGROUND: The liver X receptors (LXRs) are a family of nuclear receptor transcription factors that are activated by oxysterols and have defined roles in both lipid metabolism and cholesterol regulation. LXRs also affect antimicrobial responses and have anti-inflammatory effects in macrophages. As mice lacking LXRs are more susceptible to infection by intracellular bacteria Listeria monocytogenes and Mycobacterium tuberculosis, we hypothesized that LXR might also influence macrophage responses to the intracellular protozoan parasite Leishmania chagasi/infantum, a causative agent of visceral leishmaniasis...
November 16, 2010: PLoS Neglected Tropical Diseases
Mi-Jeong Kim, Helen C Wainwright, Michael Locketz, Linda-Gail Bekker, Gabriele B Walther, Corneli Dittrich, Annalie Visser, Wei Wang, Fong-Fu Hsu, Ursula Wiehart, Liana Tsenova, Gilla Kaplan, David G Russell
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...
July 2010: EMBO Molecular Medicine
Yanmin Hu, Robert van der Geize, Gurdyal S Besra, Sudagar S Gurcha, Alexander Liu, Manfred Rohde, Mahavir Singh, Anthony Coates
Mycobacterium tuberculosis H37Rv contains the kshA (Rv3526) and kshB (Rv3571) genes, encoding 3-ketosteroid 9alpha-hydroxylase (KSH). Consistent with their predicted roles, the DeltakshA and DeltakshB deletion mutants of M. tuberculosis H37Rv were unable to use cholesterol and 4-androstene-3,17-dione as primary carbon and energy sources. Interestingly, DeltakshA and DeltakshB mutants were also unable to metabolize the steroid substrate 5alpha-androstane-3,17-dione, whereas wild-type M. tuberculosis H37Rv could...
January 2010: Molecular Microbiology
Natasha M Nesbitt, Xinxin Yang, Patricia Fontán, Irina Kolesnikova, Issar Smith, Nicole S Sampson, Eugenie Dubnau
Mycobacterium tuberculosis, the causative agent of tuberculosis, is an intracellular pathogen that shifts to a lipid-based metabolism in the host. Moreover, metabolism of the host lipid cholesterol plays an important role in M. tuberculosis infection. We used transcriptional profiling to identify genes transcriptionally regulated by cholesterol and KstR (Rv3574), a TetR-like repressor. The fadA5 (Rv3546) gene, annotated as a lipid-metabolizing thiolase, the expression of which is upregulated by cholesterol and repressed by KstR, was deleted in M...
January 2010: Infection and Immunity
Anna Brzostek, Jakub Pawelczyk, Anna Rumijowska-Galewicz, Bozena Dziadek, Jaroslaw Dziadek
It is expected that the obligatory human pathogen Mycobacterium tuberculosis must adapt metabolically to the various nutrients available during its cycle of infection, persistence, and reactivation. Cholesterol, which is an important part of the mammalian cytoplasmic membrane, is a potential energy source. Here, we show that M. tuberculosis grown in medium containing a carbon source other than cholesterol is able to accumulate cholesterol in the free-lipid zone of its cell wall. This cholesterol accumulation decreases the permeability of the cell wall for the primary antituberculosis drug, rifampin, and partially masks the mycobacterial surface antigens...
November 2009: Journal of Bacteriology
Maurine D Miner, Jennifer C Chang, Amit K Pandey, Christopher M Sassetti, David R Sherman
Mycobacterium tuberculosis (MTB) acquisition and utilization of nutrients within the host cell is poorly understood, although it has been hypothesized that host lipids probably play an important role in MTB survival. Cholesterol has recently been identified as an important lipid for mycobacterial infection. The mce4 transport system is required for cholesterol import into bacterial cells, and deletion of mce4 locus resulted in severe attenuation in a chronic mouse model of infection. However, it has remained unclear what additional bacterial functions were required for utilization of this sterol...
June 2009: Indian Journal of Experimental Biology
Suzana Savvi, Digby F Warner, Bavesh D Kana, John D McKinney, Valerie Mizrahi, Stephanie S Dawes
Mycobacterium tuberculosis is predicted to subsist on alternative carbon sources during persistence within the human host. Catabolism of odd- and branched-chain fatty acids, branched-chain amino acids, and cholesterol generates propionyl-coenzyme A (CoA) as a terminal, three-carbon (C(3)) product. Propionate constitutes a key precursor in lipid biosynthesis but is toxic if accumulated, potentially implicating its metabolism in M. tuberculosis pathogenesis. In addition to the well-characterized methylcitrate cycle, the M...
June 2008: Journal of Bacteriology
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