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Cholesterol metabolism mycobacterium tuberculosis

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https://www.readbyqxmd.com/read/29718271/cholesterol-and-fatty-acids-grease-the-wheels-of-mycobacterium-tuberculosis-pathogenesis
#1
Kaley M Wilburn, Rachael A Fieweger, Brian C VanderVen
Tuberculosis is a distinctive disease in which the causative agent, Mycobacterium tuberculosis, can persist in humans for decades by avoiding clearance from host immunity. During infection, M. tuberculosis maintains viability by extracting and utilizing essential nutrients from the host, and this is a prerequisite for all of the pathogenic activities that are deployed by the bacterium. In particular, M. tuberculosis preferentially acquires and metabolizes host-derived lipids (fatty acids and cholesterol), and the bacterium utilizes these substrates to cause and maintain disease...
March 1, 2018: Pathogens and Disease
https://www.readbyqxmd.com/read/29593722/formation-of-foamy-macrophages-by-tuberculous-pleural-effusions-is-triggered-by-the-interleukin-10-signal-transducer-and-activator-of-transcription-3-axis-through-acat-upregulation
#2
Melanie Genoula, José Luis Marín Franco, Maeva Dupont, Denise Kviatcovsky, Ayelén Milillo, Pablo Schierloh, Eduardo Jose Moraña, Susana Poggi, Domingo Palmero, Dulce Mata-Espinosa, Erika González-Domínguez, Juan Carlos León Contreras, Paula Barrionuevo, Bárbara Rearte, Marlina Olyissa Córdoba Moreno, Adriana Fontanals, Agostina Crotta Asis, Gabriela Gago, Céline Cougoule, Olivier Neyrolles, Isabelle Maridonneau-Parini, Carmen Sánchez-Torres, Rogelio Hernández-Pando, Christel Vérollet, Geanncarlo Lugo-Villarino, María Del Carmen Sasiain, Luciana Balboa
The ability of Mycobacterium tuberculosis (Mtb) to persist in its human host relies on numerous immune evasion strategies, such as the deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM). Yet, the specific host factors leading to the foamy phenotype of Mtb-infected macrophages remain unknown. Herein, we aimed to address whether host cytokines contribute to FM formation in the context of Mtb infection. Our approach is based on the use of an acellular fraction of tuberculous pleural effusions (TB-PE) as a physiological source of local factors released during Mtb infection...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29573124/the-role-of-lipids-in-host-pathogen-interactions
#3
REVIEW
Glenn F W Walpole, Sergio Grinstein, Johannes Westman
Innate immunity relies on the effective recognition and elimination of pathogenic microorganisms. This entails sequestration of pathogens into phagosomes that promptly acquire microbicidal and degradative properties. This complex series of events, which involve cytoskeletal reorganization, membrane remodeling and the activation of multiple enzymes, is orchestrated by lipid signaling. To overcome this immune response, intracellular pathogens acquired mechanisms to subvert phosphoinositide-mediated signaling and use host lipids, notably cholesterol, as nutrients...
March 23, 2018: IUBMB Life
https://www.readbyqxmd.com/read/29475946/the-anaplerotic-node-is-essential-for-the-intracellular-survival-of-mycobacterium-tuberculosis
#4
Piyali Basu, Noor Sandhu, Apoorva Bhatt, Albel Singh, Ricardo Balhana, Irene Gobe, Nicola A Crowhurst, Tom A Mendum, Liang Gao, Jane L Ward, Michael H Beale, Johnjoe McFadden, Dany J V Beste
Enzymes at the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis, and anaplerosis. Here we used genetic, biochemical, and 13 C isotopomer analysis to characterize the role of the enzymes at the ANA node in intracellular survival of the world's most successful bacterial pathogen, Mycobacterium tuberculosis ( Mtb ). We show that each of the four ANA enzymes, pyruvate carboxylase (PCA), PEP carboxykinase (PCK), malic enzyme (MEZ), and pyruvate phosphate dikinase (PPDK), performs a unique and essential metabolic function during the intracellular survival of Mtb...
April 13, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29367626/il-36-lxr-axis-modulates-cholesterol-metabolism-and-immune-defense-to-mycobacterium-tuberculosis
#5
Fadhil Ahsan, Jeroen Maertzdorf, Ute Guhlich-Bornhof, Stefan H E Kaufmann, Pedro Moura-Alves
Mycobacterium tuberculosis (Mtb) is a life-threatening pathogen in humans. Bacterial infection of macrophages usually triggers strong innate immune mechanisms, including IL-1 cytokine secretion. The newer member of the IL-1 family, IL-36, was recently shown to be involved in cellular defense against Mtb. To unveil the underlying mechanism of IL-36 induced antibacterial activity, we analyzed its role in the regulation of cholesterol metabolism, together with the involvement of Liver X Receptor (LXR) in this process...
January 24, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29247215/the-transcriptome-of-mycobacterium-tuberculosis-in-a-lipid-rich-dormancy-model-through-rnaseq-analysis
#6
Diana A Aguilar-Ayala, Laurentijn Tilleman, Filip Van Nieuwerburgh, Dieter Deforce, Juan Carlos Palomino, Peter Vandamme, Jorge A Gonzalez-Y-Merchand, Anandi Martin
Tuberculosis (TB) is currently the number one killer among infectious diseases worldwide. Lipids are abundant molecules during the infectious cycle of Mycobacterium tuberculosis (Mtb) and studies better mimicking its actual metabolic state during pathogenesis are needed. Though most studies have focused on the mycobacterial lipid metabolism under standard culture conditions, little is known about the transcriptome of Mtb in a lipid environment. Here we determined the transcriptome of Mtb H37Rv in a lipid-rich environment (cholesterol and fatty acid) under aerobic and hypoxic conditions, using RNAseq...
December 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29067283/small-molecule-mediated-restoration-of-mitochondrial-function-augments-anti-mycobacterial-activity-of-human-macrophages-subjected-to-cholesterol-induced-asymptomatic-dyslipidemia
#7
Suman Asalla, Krishnaveni Mohareer, Sharmistha Banerjee
Mycobacterium tuberculosis ( M.tb) infection manifests into tuberculosis (TB) in a small fraction of the infected population that comprises the TB susceptible group. Identifying the factors potentiating susceptibility to TB persistence is one of the prime agenda of TB control programs. Recently, WHO recognized diabetes as a risk factor for TB disease progression. The closely related pathological state of metabolic imbalance, dyslipidemia, is yet another emerging risk factor involving deregulation in host immune responses...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28988960/pdim-and-sl1-accumulation-in-mycobacterium-tuberculosis-is-associated-with-mce4a-expression
#8
Pooja Singh, Rajesh Sinha, Gaurav Tyagi, Naresh Kumar Sharma, Neeraj K Saini, Amita Chandolia, Ashok Kumar Prasad, Mandira Varma-Basil, Mridula Bose
Lipid metabolism forms the heart and soul of Mycobacterium tuberculosis life cycle. Starting from macrophage invasion at cholesterol rich micro-domains to a sustainable survival for infection by utilizing cholesterol, Mycobacterium displays the nexus of metabolic pathways around host derived lipids. mce4 operon acts as cholesterol import system in M. tuberculosis and here we demonstrate role of mce4A gene of this operon in cholesterol catabolism. Here M. tuberculosis H37Rv overexpressing Rv3499c (mce4A) recombinant was used as a model to decipher the metabolic flux during intake and utilization of host lipids by mycobacteria...
February 5, 2018: Gene
https://www.readbyqxmd.com/read/28771131/comparative-proteomic-profiles-reveal-characteristic-mycobacterium-tuberculosis-proteins-induced-by-cholesterol-during-dormancy-conditions
#9
Lazaro Garcia-Morales, Lizbel Leon-Solis, Irma E Monroy-Muñoz, Moises Talavera-Paulin, Jeanet Serafin-López, Iris Estrada-Garcia, Sandra Rivera-Gutierrez, Jorge F Cerna-Cortes, Addy C Helguera-Repetto, Jorge A Gonzalez-Y-Merchand
Cholesterol has been reported to play an important role during Mycobacterium tuberculosis infection and during its dormant state inside the host. We present the determination of proteomic profiles of M. tuberculosis H37Rv in the presence of cholesterol as the sole carbon source under exponential growth and in two in vitro dormancy phases (NRP1 and NRP2). Using 2D-PAGE, we detected that M. tuberculosis expressed a high diversity of proteins in both exponential and non-replicative phases. We also found that cholesterol was involved in the overexpression of some proteins related to sulfur metabolism (CysA2), electron transport (FixB), cell wall synthesis (Ald), iron storage (BfrB), protein synthesis (Tig and EF-Tu) and dormancy maintenance (HspX and TB 31...
August 4, 2017: Microbiology
https://www.readbyqxmd.com/read/28464471/chemical-activation-of-adenylyl-cyclase-rv1625c-inhibits-growth-of-mycobacterium-tuberculosis-on-cholesterol-and-modulates-intramacrophage-signaling
#10
Richard M Johnson, Guangchun Bai, Christopher M DeMott, Nilesh K Banavali, Christine R Montague, Caroline Moon, Alexander Shekhtman, Brian VanderVen, Kathleen A McDonough
Mycobacterium tuberculosis (Mtb) uses a complex 3', 5'-cyclic AMP (cAMP) signaling network to sense and respond to changing environments encountered during infection, so perturbation of cAMP signaling might be leveraged to disrupt Mtb pathogenesis. However, understanding of cAMP signaling pathways is hindered by the presence of at least 15 distinct adenylyl cyclases (ACs). Recently, the small molecule V-58 was shown to inhibit Mtb replication within macrophages and stimulate cAMP production in Mtb. Here we determined that V-58 rapidly and directly activates Mtb AC Rv1625c to produce high levels of cAMP regardless of the bacterial environment or growth medium...
July 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28250431/novel-protein-acetyltransferase-rv2170-modulates-carbon-and-energy-metabolism-in-mycobacterium-tuberculosis
#11
Wonsik Lee, Brian C VanderVen, Suzanne Walker, David G Russell
Recent data indicate that the metabolism of Mycobacterium tuberculosis (Mtb) inside its host cell is heavily dependent on cholesterol and fatty acids. Mtb exhibits a unique capacity to co-metabolize different carbon sources and the products from these substrates are compartmentalized metabolically. Isocitrate lies at one of the key nodes of carbon metabolism and can feed into either the glyoxylate shunt (via isocitrate lyase) or the TCA cycle (via isocitrate dehydrogenase (ICDH) activity) and we sought to better understand the regulation at this junction...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28217856/molecular-characterization-of-a-new-gene-cluster-for-steroid-degradation-in-mycobacterium-smegmatis
#12
Lorena Fernández-Cabezón, Esther García-Fernández, Beatriz Galán, José L García
The C-19 steroids 4-androstene-3,17-dione (AD), 1,4-androstadiene-3,17-dione (ADD) or 9α-hydroxy-4-androstene-3,17-dione (9OH-AD), which have been postulated as intermediates of the cholesterol catabolic pathway in Mycobacterium smegmatis, cannot be used as sole carbon and energy sources by this bacterium. Only the ΔkstR mutant which constitutively expresses the genes repressed by the KstR regulator can metabolize AD and ADD with severe difficulties but still cannot metabolize 9OH-AD, suggesting that these compounds are not true intermediates but side products of the cholesterol pathway...
July 2017: Environmental Microbiology
https://www.readbyqxmd.com/read/28002883/cholesterol-metabolism-a-potential-therapeutic-target-in-mycobacteria
#13
REVIEW
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
https://www.readbyqxmd.com/read/27856345/drug-targeting-of-heme-proteins-in-mycobacterium-tuberculosis
#14
REVIEW
Kirsty J McLean, Andrew W Munro
TB, caused by the human pathogen Mycobacterium tuberculosis (Mtb), causes more deaths than any other infectious disease. Iron is crucial for Mtb to infect the host and to sustain infection, with Mtb encoding large numbers of iron-binding proteins. Many of these are hemoproteins with key roles, including defense against oxidative stress, cellular signaling and regulation, host cholesterol metabolism, and respiratory processes. Various heme enzymes in Mtb are validated drug targets and/or products of genes essential for bacterial viability or survival in the host...
March 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/27847019/expression-profile-of-mce4-operon-of-mycobacterium-tuberculosis-following-environmental-stress
#15
Nisha Rathor, Kushal Garima, Naresh Kumar Sharma, Anshika Narang, Mandira Varma-Basil, Mridula Bose
BACKGROUND: The mce4 operon is one of the four mce operons with eight genes (yrbE4A, yrbE4B, mce4A, mce4B, mce4C, mce4D, mce4E and mce4F) of Mycobacterium tuberculosis. It expresses in the later phase of infection and imports cholesterol for long term survival of the bacilli. To cause latent infection, M. tuberculosis undergoes metabolic reprogramming of its genes to survive in the hostile environment like low availability of oxygen and nutrition depletion inside the host. OBJECTIVE: To analyze real time expression profile of mce4 operon under various stress conditions...
September 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/27804278/mycobacterium-smegmatis-is-a-suitable-cell-factory-for-the-production-of-steroidic-synthons
#16
Beatriz Galán, Iria Uhía, Esther García-Fernández, Igor Martínez, Esther Bahíllo, Juan L de la Fuente, José L Barredo, Lorena Fernández-Cabezón, José L García
A number of pharmaceutical steroid synthons are currently produced through the microbial side-chain cleavage of natural sterols as an alternative to multi-step chemical synthesis. Industrially, these synthons have been usually produced through fermentative processes using environmental isolated microorganisms or their conventional mutants. Mycobacterium smegmatis mc2 155 is a model organism for tuberculosis studies which uses cholesterol as the sole carbon and energy source for growth, as other mycobacterial strains...
January 2017: Microbial Biotechnology
https://www.readbyqxmd.com/read/27718364/uptake-and-metabolism-of-fluorescent-steroids-by-mycobacterial-cells
#17
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 H37 Rv and M. smegmatis mc2 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
https://www.readbyqxmd.com/read/27677638/discovery-and-biophysical-evaluation-of-first-low-nanomolar-hits-targeting-cyp125-of-m-%C3%A2-tuberculosis
#18
Christian Brengel, Andreas Thomann, Alexander Schifrin, Jens Eberhard, Rolf W Hartmann
Tuberculosis, which is predominantly caused by Mycobacterium tuberculosis (Mtb), is still the most lethal bacterial infection with 1.5 million casualties in 2014. Moreover, the fact that the appearance of resistant mutants and long-term treatment are coupled with economic problems in developing countries hampers an efficient therapy. Interference with the essential cholesterol metabolism of Mtb could be a promising novel strategy to fight Mtb infections. CYP125, a P450 enzyme in Mtb, has been shown to play an important role in this metabolic pathway...
September 28, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27672155/inhibiting-mycobacterium-tuberculosis-within-and-without
#19
REVIEW
Stewart T Cole
Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. Initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in clinical trials...
November 5, 2016: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/27164097/genome-wide-transcriptome-profiling-of-mycobacterium-smegmatis-mc%C3%A2-155-cultivated-in-minimal-media-supplemented-with-cholesterol-androstenedione-or-glycerol
#20
Qun Li, Fanglan Ge, Yunya Tan, Guangxiang Zhang, Wei Li
Mycobacterium smegmatis strain MC² 155 is an attractive model organism for the study of M. tuberculosis and other mycobacterial pathogens, as it can grow well using cholesterol as a carbon resource. However, its global transcriptomic response remains largely unrevealed. In this study, M. smegmatis MC² 155 cultivated in androstenedione, cholesterol and glycerol supplemented media were collected separately for a RNA-Sequencing study. The results showed that 6004, 6681 and 6348 genes were expressed in androstenedione, cholesterol and glycerol supplemented media, and 5891 genes were expressed in all three conditions, with 237 specially expressed in cholesterol added medium...
May 7, 2016: International Journal of Molecular Sciences
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