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macrophage tuberculosis

Shivraj M Yabaji, Alok K Mishra, Aditi Chatterjee, Rikesh K Dubey, Kanchan Srivastava, Kishore K Srivastava
Early secretory antigenic target protein (ESAT-6) is an important virulent factor which plays a crucial role in Mycobacterium tuberculosis (MTB) pathogenesis. Here, we demonstrate the role of ESAT-6 in phagocytosis and intracellular survival of mycobacteria through a mechanism mediated by regulation of a host protein; Peroxiredoxin-1 (Prdx-1). Prdx-1 is an anti-apoptotic and stress response protein which protects cells from damage by ROS and H2O2 stresses. The J774 A.1 cells infected with MTB or over-expressing ESAT-6 through eukaryotic promoter vector showed elevated expression of Prdx-1...
October 12, 2017: Biochemical and Biophysical Research Communications
Tobias Dallenga, Urska Repnik, Björn Corleis, Jacqueline Eich, Rudolph Reimer, Gareth W Griffiths, Ulrich E Schaible
Neutrophils represent the main infected cell population in the lungs of active tuberculosis patients. Efficient removal of infected and dying neutrophils is required to protect the surrounding tissue from bioactive neutrophil molecules and subsequent pathological sequelae. While the removal of apoptotic M. tuberculosis (Mtb)-infected cells, or efferocytosis, is considered beneficial for host defense, little is known about Mtb-infected necrotic neutrophils. We found that Mtb induces necrosis of human neutrophils in an ESX-1-dependent manner, and neutrophil-produced reactive oxygen species (ROS) drive this necrosis...
October 11, 2017: Cell Host & Microbe
Xiang He, He-Wei Jiang, Hong Chen, Hainan Zhang, Yin Liu, Zhao-Wei Xu, Fanlin Wu, Shu-Juan Guo, Jing-Li Hou, Mingkun Yang, Wei Yan, Jiaoyu Deng, Lijun Bi, Xian-En Zhang, Sheng-Ce Tao
Mycobacterium tuberculosis (Mtb) has evolved multiple strategies to counter the human immune system. The effectors of Mtb play important roles in the interactions with the host. However, due to the lack of highly efficient strategies, there are only a handful of known Mtb effectors, thus hampering our understanding of Mtb pathogenesis. In this study, we probed Mtb proteome microarray with biotinylated whole-cell lysates of human macrophages, identifying 27 Mtb membrane proteins and secreted proteins that bind to macrophage proteins...
October 10, 2017: Molecular & Cellular Proteomics: MCP
Maria V Papadopoulou, William D Bloomer, Howard S Rosenzweig
Twenty three 3-nitrotriazole- and five nitroimidazole-based compounds, mostly amides, were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv (Mtb H37Rv) under aerobic or low oxygen conditions, intracellular activity in murine J774 macrophages or THP-1 cells, activity against resistant Mtb strains as well as cytotoxicity in normal cells. Compounds with a Minimum Inhibitory Concentration (MIC) less than 10μM and 10-50μM were characterized as active and moderately active, respectively, whereas compounds with a MIC >50μM were characterized inactive...
September 28, 2017: Bioorganic & Medicinal Chemistry
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
Fransisca Leonard, Ngan P Ha, Preeti Sule, Jenolyn F Alexander, David E Volk, Ganesh L R Lokesh, Xuewu Liu, Jeffrey D Cirillo, David G Gorenstein, Jinyun Yuan, Soumya Chatterjee, Edward A Graviss, Biana Godin
Worldwide, tuberculosis (TB) remains one of the most prevalent infectious diseases causing morbidity and death in >1.5 million patients annually. Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, usually resides in the alveolar macrophages. Current tuberculosis treatment methods require more than six months, and low compliance often leads to therapeutic failure and multidrug resistant strain development. Critical to improving TB-therapy is shortening treatment duration and increasing therapeutic efficacy...
October 4, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
Murugesan V S Rajaram, Eusondia Arnett, Abul K Azad, Evelyn Guirado, Bin Ni, Abigail D Gerberick, Li-Zhen He, Tibor Keler, Lawrence J Thomas, William P Lafuse, Larry S Schlesinger
Despite its prominent role as a C-type lectin (CTL) pattern recognition receptor, mannose receptor (MR, CD206)-specific signaling molecules and pathways are unknown. The MR is highly expressed on human macrophages, regulating endocytosis, phagocytosis, and immune responses and mediating Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages, thereby limiting phagosome-lysosome (P-L) fusion. We identified human MR-associated proteins using phosphorylated and non-phosphorylated MR cytoplasmic tail peptides...
October 3, 2017: Cell Reports
Martin T Speth, Urska Repnik, Elisabeth Müller, Julia Spanier, Ulrich Kalinke, Alexandre Corthay, Gareth Griffiths
The attenuated live vaccine strain Bacille Calmette-Guérin (BCG) is currently the only available vaccine against tuberculosis (TB), but is largely ineffective against adult pulmonary TB, the most common disease form. This is in part due to BCG's ability to interfere with the host innate immune response, a feature that might be targeted to enhance the potency of this vaccine. Here, we investigated the ability of chitosan-based nanoparticles (pIC-NPs) containing polyinosinic-polycytidylic acid (poly(I:C)), an inducer of innate immunity via Toll-like receptor 3 (TLR3) to enhance the immunogenicity of BCG in mouse bone marrow-derived macrophages (BMDM) in vitro...
October 3, 2017: Molecular Pharmaceutics
Naser F Al-Tannak, Oludotun A Phillips
Twelve N-substituted-glycinyl triazolyl oxazolidinone derivatives were screened for antimycobacterial activity against susceptible (Mycobacteriumtuberculosis (Mtb) H37Rv) and resistant (isoniazid (INH)-resistant Mtb (SRI 1369), rifampin (RMP)-resistant Mtb (SRI 1367), and ofloxacin (OFX)-resistant Mtb (SRI 4000)) Mtb strains. Most of the compounds showed moderate to strong antimycobacterial activity against all strains tested, with minimum inhibitory concentration (MIC) value ranges of 0.5-11.5, 0.056-11.6, 0...
October 2, 2017: Scientia Pharmaceutica
Landry Blanc, Martine Gilleron, Jacques Prandi, Ok-Ryul Song, Mi-Seon Jang, Brigitte Gicquel, Daniel Drocourt, Olivier Neyrolles, Priscille Brodin, Gérard Tiraby, Alain Vercellone, Jérôme Nigou
Mycobacterium tuberculosis is a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by which M. tuberculosis circumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate of M. tuberculosis of the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-κB, a key regulator of innate immunity...
October 2, 2017: Proceedings of the National Academy of Sciences of the United States of America
Stefan Köster, Sandeep Upadhyay, Pallavi Chandra, Kadamba Papavinasasundaram, Guozhe Yang, Amir Hassan, Steven J Grigsby, Ekansh Mittal, Heidi S Park, Victoria Jones, Fong-Fu Hsu, Mary Jackson, Christopher M Sassetti, Jennifer A Philips
Mycobacterium tuberculosis' success as a pathogen comes from its ability to evade degradation by macrophages. Normally macrophages clear microorganisms that activate pathogen-recognition receptors (PRRs) through a lysosomal-trafficking pathway called "LC3-associated phagocytosis" (LAP). Although Mtuberculosis activates numerous PRRs, for reasons that are poorly understood LAP does not substantially contribute to Mtuberculosis control. LAP depends upon reactive oxygen species (ROS) generated by NADPH oxidase, but Mtuberculosis fails to generate a robust oxidative response...
September 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
A Theron, R L Roth, H Hoppe, C Parkinson, C W van der Westhuyzen, S Stoychev, I Wiid, R D Pietersen, B Baker, C P Kenyon
Glutamine synthetase is a ubiquitous central enzyme in nitrogen metabolism that is controlled by up to four regulatory mechanisms, including adenylylation of some or all of the twelve subunits by adenylyl transferase. It is considered a potential therapeutic target for the treatment of tuberculosis, being essential for the growth of Mycobacterium tuberculosis, and is found extracellularly only in the pathogenic Mycobacterium strains. Human glutamine synthetase is not regulated by the adenylylation mechanism, so the adenylylated form of bacterial glutamine synthetase is of particular interest...
2017: PloS One
Norbert Reiling, Susanne Homolka, Thomas A Kohl, Christine Steinhäuser, Katharina Kolbe, Stefan Schütze, Julius Brandenburg
Pathogenic mycobacteria of the Mycobacterium tuberculosis complex (MTBC) have co-evolved with their individual hosts and are able to transform the hostile environment of the macrophage into a permissive cellular habitat. The impact of MTBC genetic variability has long been considered largely unimportant in TB pathogenesis. Members of the MTBC can now be distinguished into three major phylogenetic groups consisting of 7 phylogenetic lineages and more than 30 so called sub-lineages/subgroups. MTBC genetic diversity indeed influences the transmissibility and virulence of clinical MTBC isolates as well as the immune response and the clinical outcome...
September 14, 2017: International Journal of Medical Microbiology: IJMM
Yongyan Wu, Zekun Guo, Fayang Liu, Kezhen Yao, Mingqing Gao, Yan Luo, Yong Zhang
Tuberculosis remains a leading health problem worldwide and still accounts for about 1.3 million deaths annually. Expression of the mouse Sp110 nuclear body protein (Sp110) upregulates the apoptotic pathway, which plays an essential role in enhancing host immunity to Mycobacterium tuberculosis (Mtb). However, the mechanism of this upregulation is unclear. Here, we have identified 253 proteins in mouse macrophages that interact with Sp110, of which 251 proteins were previously uncharacterized. The results showed that Sp110 interacts with heat shock protein 5 (Hspa5) to activate endoplasmic reticulum (ER) stress-induced apoptosis, and that this is essential for Sp110 enhanced macrophage resistance to Mtb...
September 8, 2017: Oncotarget
Dhemerson Souza de Lima, Vinicius C L Nunes, Mauricio M Ogusku, Aya Sadahiro, Alessandra Pontillo, Bruna de Cunha Alencar
Siglec-1/CD169 is a sialoadhesin expressed by macrophages thought to function in cell-to-cell interactions. In the lung, the expression of Siglec-1 is specific for alveolar macrophages and single nucleotide polymorphisms (SNPs) in SIGLEC1 have been recently associated with asthma severity. Taking in account the role of alveolar macrophages in the control of M. tuberculosis and the poor literature about the contribution of SIGLEC1 genetics in M. tuberculosis susceptibility and development of pulmonary active TB, selected SNPs in SIGLEC1 were analysed in a case/control cohort from a TB endemic area of Brazil Amazon...
September 28, 2017: Infection, Genetics and Evolution
Lerato Hlaka, Michael-Jon Rosslee, Mumin Ozturk, Santosh Kumar, Suraj P Parihar, Frank Brombacher, Abedawn I Khalaf, Katharine C Carter, Fraser J Scott, Colin J Suckling, Reto Guler
Objectives: The slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis ( Mtb ) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor groove binders (MGBs) have previously revealed promising antimicrobial activity against various infectious agents; however, they have not yet been screened against Mtb ...
September 18, 2017: Journal of Antimicrobial Chemotherapy
Séverine Evrard, Philippe Caprasse, Pierre Gavage, Myriam Vasbien, Jean Radermacher, Marie-Pierre Hayette, Rosalie Sacheli, Marjan Van Esbroeck, Lieselotte Cnops, Eric Firre, Laurent Médart, Filip Moerman, Jean-Marc Minon
Case report We report the case of a young Cameroonian woman who presented with cough, hyperthermia, weight loss, pancytopenia, and hepatosplenomegaly. A positive HIV serology was discovered and a chest radiography revealed a 'miliary pattern'. Bone marrow aspiration pointed out yeast inclusions within macrophages. Given the morphological aspect, the clinical presentation and immunosuppression, histoplasmosis was retained as a working hypothesis. Antiretroviral and amphotericin B treatments were promptly initiated...
September 28, 2017: Acta Clinica Belgica
Christophe J Queval, Ok-Ryul Song, Jean-Philippe Carralot, Jean-Michel Saliou, Antonino Bongiovanni, Gaspard Deloison, Nathalie Deboosère, Samuel Jouny, Raffaella Iantomasi, Vincent Delorme, Anne-Sophie Debrie, Sei-Jin Park, Joana Costa Gouveia, Stanislas Tomavo, Roland Brosch, Akihiko Yoshimura, Edouard Yeramian, Priscille Brodin
Pathogens have evolved a range of mechanisms to counteract host defenses, notably to survive harsh acidic conditions in phagosomes. In the case of Mycobacterium tuberculosis, it has been shown that regulation of phagosome acidification could be achieved by interfering with the retention of the V-ATPase complexes at the vacuole. Here, we present evidence that M. tuberculosis resorts to yet another strategy to control phagosomal acidification, interfering with host suppressor of cytokine signaling (SOCS) protein functions...
September 26, 2017: Cell Reports
Deepti Verma, Venkata Ramanarao Parasa, Johanna Raffetseder, Mihaela Martis, Ratnesh B Mehta, Mihai Netea, Maria Lerm
The reason for the largely variable protective effect against TB of the vaccine Bacille Calmette-Guerin (BCG) is not understood. In this study, we investigated whether epigenetic mechanisms are involved in the response of immune cells to the BCG vaccine. We isolated peripheral blood mononuclear cells (PBMCs) from BCG-vaccinated subjects and performed global DNA methylation analysis in combination with functional assays representative of innate immunity against Mycobacterium tuberculosis infection. Enhanced containment of replication was observed in monocyte-derived macrophages from a sub-group of BCG-vaccinated individuals (identified as 'responders')...
September 26, 2017: Scientific Reports
K Thiam, J M A N Sagne, E H M Ndiaye, M F Cissé, F B R Mbaye, N O Touré, Y Dia Kane, A Diatta, S Niang, U D Kombila, S Dia, M Ndao, W Ka
We report the case of a 31-year-old immunocompetent woman residing in Senegal, with localized microscopy-proved pulmonary tuberculosis, complicated by macrophage activation syndrome and associated with viral hepatitis B, identified due to hepatic cytolysis and a bicytopenia.
August 1, 2017: Médecine et Santé Tropicales
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