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Tuberculosis AND cholesterol

Piyali Basu, Noor Sanhu, Apoorva Bhatt, Albel Singh, Ricardo Balhana, Irene Gobe, Nicola A Crowhurst, Tom A Mendum, Liang Gao, Jane L Ward, Mike Beale, Johnjoe McFadden, Dany Jv Beste
Enzymes at the PEP-pyruvate-oxaloacetate or anaplerotic (ANA) node control the metabolic flux to glycolysis, gluconeogenesis and anaplerosis. Here we use genetic, biochemical and13 C isotopomer analysis to characterize the role of the enzymes at the ANA node during the 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   We show that in addition to PCK, intracellular Mtb requires PPDK as an alternative gateway into gluconeogenesis...
February 23, 2018: Journal of Biological Chemistry
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
Shagufta Khan, Faez Iqbal Khan, Taj Mohammad, Parvez Khan, Gulam Mustafa Hasan, Kevin A Lobb, Asimul Islam, Faizan Ahmad, Md Imtaiyaz Hassan
Mammalian cell entry protein (Mce4A) is a member of MCE-family, and is being considered as a potential drug target of Mycobacterium tuberculosis infection because it is required for invasion and latent survival of pathogen by utilizing host's cholesterol. In the present study, we performed molecular docking followed by 100 ns MD simulation studies to understand the mechanism of interaction of Mce4A to the cholesterol derivatives and probucol. The selected ligands, cholesterol, 25-hydroxycholesterol, 5-cholesten-3β-ol-7-one and probucol bind to the predicted active site cavity of Mce4A, and complexes remain stable during entire simulation of 100 ns...
January 9, 2018: International Journal of Biological Macromolecules
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
Gebremedhin Gebremicael, Yemane Amare, Feyissa Challa, Atsbeha Gebreegziabxier, Girmay Medhin, Mistire Wolde, Desta Kassa
Background: Understanding whether the preceding low lipid profile leads to active tuberculosis (TB) or active TB leads to low lipid profile is crucial. Methods: Lipid profile concentrations were determined from 159 study participants composed of 93 active TB patients [44 HIV coinfected (HIV+TB+) and 49 HIV negative (HIV-TB+)], 41 tuberculin skin test (TST) positive cases [17 HIV coinfected (HIV+TST+) and 24 HIV negative (HIV-TST+)], and 25 healthy controls (HIV-TST-)...
2017: International Journal of Chronic Diseases
Mokhitli Morake, Dina Coertzen, Andile Ngwane, Johannes F Wentzel, Ho Ning Wong, Frans J Smit, Lyn-Marie Birkholtz, Ray-Dean Pietersen, Bienyameen Baker, Ian Wiid, David D N'Da, Richard K Haynes
To evaluate the feasibility of developing drugs that may be active against both malaria and tuberculosis (TB) by using in part putative cholesterol transporters in the causative pathogens and through enhancement of passive diffusion in granulomatous TB, artemisinin-cholesterol conjugates were synthesized by connecting the component molecules through various linkers. The compounds were screened in vitro against Plasmodium falciparum (Pf) and Mycobacterium tuberculosis (Mtb). Antimalarial activities (IC50 ) against Pf drug-sensitive NF54, and drug-resistant K1 and W2 strains ranged from 0...
January 8, 2018: ChemMedChem
Stephanie Gilbert, LaChae Hood, Stephen Y K Seah
The heteromeric acyl-CoA dehydrogenase, FadE28-FadE29 and the enoyl CoA hydratase ChsH1-ChsH2, encoded by genes within the intracellular growth (igr) operon of Mycobacterium tuberculosis, catalyze the dehydrogenation of the 3-carbon side chain cholesterol metabolite, 3-OPC-CoA, and subsequent hydration of the product 3-oxo-4,17-pregnadiene-20-carboxyl-CoA (3-OPDC-CoA) to form 17-hydroxy-3-oxo-4-pregnene-20-carboxyl-CoA (17-HOPC-CoA). The gene downstream of chsH2, ltp2, was expressed in recombinant Rhodococcus jostii RHA1 in combination with other genes within the igr operon...
November 6, 2017: Journal of Bacteriology
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
Lelia Lavalett, Hector Rodriguez, Hector Ortega, Wolfgang Sadee, Larry S Schlesinger, Luis F Barrera
Alveolar macrophages (AMs) are major targets of Mycobacterium tuberculosis (Mtb) infection, critical during the progression of active tuberculosis (TB). The complex immunopathology of TB generates diverse microenvironments in the lung, which shape immune responses by AMs. In the current study, we perform whole genome microarray transcriptional profiling on RNA isolated from AMs from TB patients (AMsTB) compared to AMs from control subjects (AMsCT) using bronchoalveolar lavage (BAL). Our hypothesis was that systemic effects on the local lung microenvironment during TB affect the transcriptional response of AMsTB...
December 2017: Tuberculosis
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...
October 5, 2017: Gene
Valnês S Rodrigues-Junior, Luciana Cintra, Pablo Machado, Adílio Dadda, Luiz Augusto Basso, Ana Carolina Cintra Nunes Mafra, Alexandre Holthausen Campos, Maria Martha Campos, Diógenes Santiago Santos
IQG-607 is an anti-tuberculosis drug candidate, with a promising safety and efficacy profile in models of tuberculosis infection both in vitro and in vivo. Here, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in minipigs. Single oral administration of IQG-607 (220 mg/kg) to female and male minipigs did not result in any morbidity or mortality. No gross lesions were observed in the minipigs at necropsy. Repeated administration of IQG 607 (65, 30, or 15 mg/kg), given orally, for 90 days, in both male and female animals did not cause any mortality and no significant body mass alteration...
August 23, 2017: Regulatory Toxicology and Pharmacology: RTP
Lauren Philips, Janicke Visser, Daan Nel, Renée Blaauw
BACKGROUND: The existence of a bi-directional relationship between tuberculosis (TB) and insulin resistance (IR)/diabetes has been alluded to in literature. Although diabetes has been linked to increased tuberculosis risk, the relationship between tuberculosis as a causative factor for IR remains unclear. The study aimed to determine if an association existed between tuberculosis and IR development in adults with newly diagnosed pulmonary tuberculosis at baseline. It was additionally aimed to document changes in IR status during TB follow-up periods...
August 15, 2017: BMC Infectious Diseases
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
Julia García-Fernández, Kadamba Papavinasasundaram, Beatriz Galán, Christopher M Sassetti, José L García
Mycobacterium smegmatis contains 6 homologous mce (mammalian cell entry) operons which have been proposed to encode ABC-like import systems. The mce operons encode up to 10 different proteins of unknown function that are not present in conventional ABC transporters. We have analysed the consequences of individually deleting each of the genes of the mce4 operon of M. smegmatis, which mediates the transport of cholesterol. None of the mce4 mutants were able to grow in cholesterol suggesting that all these genes are required for its uptake and that none of them can be replaced by the homologous genes of the other mce operons...
September 2017: Environmental Microbiology
Evgeniya V Nazarova, Christine R Montague, Thuy La, Kaley M Wilburn, Neelima Sukumar, Wonsik Lee, Shannon Caldwell, David G Russell, Brian C VanderVen
Pathogenic bacteria have evolved highly specialized systems to extract essential nutrients from their hosts. Mycobacterium tuberculosis (Mtb) scavenges lipids (cholesterol and fatty acids) to maintain infections in mammals but mechanisms and proteins responsible for the import of fatty acids in Mtb were previously unknown. Here, we identify and determine that the previously uncharacterized protein Rv3723/LucA, functions to integrate cholesterol and fatty acid uptake in Mtb. Rv3723/LucA interacts with subunits of the Mce1 and Mce4 complexes to coordinate the activities of these nutrient transporters by maintaining their stability...
June 27, 2017: ELife
Qi Gao, Xinfang Dong, Yanping Luo, Guochao Zhang, Jinyu Shan, Qian Wang, Qi He, Lifeng Zhang, Jingqiu Wang, Bingdong Zhu, Xingming Ma
The lectin pathway, one of the complement cascade systems, provides the primary line of defense against invading pathogens. The serine protease of MASP-2 plays an essential role in complement activation of the lectin pathway. The C-terminal segment of MASP-2 is comprised of the CCP1-CCP2-SP domains, and is the crucial catalytic segment. However, what is the effect of CCP1-CCP2-SP domains in controlling chronic infection is unknown. In order to evaluate the potential impact of CCP1-CCP2-SP domains on tuberculosis, we constructed the human MASP-2 CCP1/2SP, CCP2SP and SP recombinant plasmids, and delivered these plasmids by DNA-DOTAP:cholesterol cationic nanolipoplexes to BCG-infected mice...
May 31, 2017: Microbial Pathogenesis
Suhail Ahmed Almani, Tariq Zaffar Shaikh, Haji Khan Khoharo, Ikramuddin Ujjan
BACKGROUND: Pulmonary tuberculosis (PTB) is a chronic granulomatous disease caused by Mycobacterium tuberculosis. The present study determined the serum human enolase-2 (ENO-2), high-sensitive C-reactive protein (hs-CRP), and serum cholesterol levels as biological marker of disease activity and treatment response in smear-positive drug-naïve PTB. MATERIALS AND METHODS: This case-control study was done in the Department of Medicine, Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro/Hyderabad, Sindh, from January 2015 to April 2016...
2017: Journal of Research in Medical Sciences: the Official Journal of Isfahan University of Medical Sciences
Cesar A Prada-Medina, Kiyoshi F Fukutani, Nathella Pavan Kumar, Leonardo Gil-Santana, Subash Babu, Flávio Lichtenstein, Kim West, Shanmugam Sivakumar, Pradeep A Menon, Vijay Viswanathan, Bruno B Andrade, Helder I Nakaya, Hardy Kornfeld
Comorbid diabetes mellitus (DM) increases tuberculosis (TB) risk and adverse outcomes but the pathological interactions between DM and TB remain incompletely understood. We performed an integrative analysis of whole blood gene expression and plasma analytes, comparing South Indian TB patients with and without DM to diabetic and non-diabetic controls without TB. Luminex assay of plasma cytokines and growth factors delineated a distinct biosignature in comorbid TBDM in this cohort. Transcriptional profiling revealed elements in common with published TB signatures from cohorts that excluded DM...
May 17, 2017: Scientific Reports
Vincent Yi-Fong Su, Wei-Juin Su, Yung-Feng Yen, Sheng-Wei Pan, Pei-Hung Chuang, Jia-Yih Feng, Kun-Ta Chou, Kuang-Yao Yang, Yu-Chin Lee, Tzeng-Ji Chen
BACKGROUND: Statins are widely used to lower cholesterol levels and cardiovascular risk. Further, studies have shown that statins may decrease the risks of infectious diseases and infection-related mortality; however, the association between statin use and active TB disease remains unclear. METHODS: Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study. Patients taking statins between 2000 and 2013, without antecedent TB disease, were included...
September 2017: Chest
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
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