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M.tuberculosis immune

M K Khan, M N Islam, J Ferdous, M M Alam
Tuberculosis (TB) is a progressive granulomatous infectious disease caused by the gram positive, acid fast bacilli classified under the genus Mycobacterium. Tuberculosis in human is mostly by Mycobacterium tuberculosis and primarily affects lungs causing pulmonary tuberculosis. It can also affect intestine, meninges, bones, joints, lymph nodes, skin and other tissues of the body causing extra-pulmonary tuberculosis. Human TB is transmitted mainly through droplet infection and droplet nuclei. Infection of human with M...
January 2019: Mymensingh Medical Journal: MMJ
Ekta Lachmandas, Clare Eckold, Julia Böhme, Valerie A C M Koeken, Mardiana Binte Marzuki, Bastiaan Blok, Rob J W Arts, Jinmiao Chen, Karen W W Teng, Jacqueline Ratter, Elise J Smolders, Corina van den Heuvel, Rinke Stienstra, Hazel M Dockrell, Evan Newell, Mihai G Netea, Amit Singhal, Jacqueline M Cliff, Reinout van Crevel
Background: Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on human host responses to Mycobacterium tuberculosis. Methods: We investigated in-vitro and in-vivo effects of metformin in humans. Results: Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in-vitro cellular metabolism whilst inhibiting the mammalian target of rapamycin (mTOR) targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation, and increased phagocytosis...
February 12, 2019: Journal of Infectious Diseases
Kee Woong Kwon, Hong-Hee Choi, Seung Jung Han, Jong-Seok Kim, Woo Sik Kim, Hongmin Kim, Lee-Han Kim, Soon Myung Kang, Jaehun Park, Sung Jae Shin
Bacillus Calmette-Guerin vaccine confers insufficient pulmonary protection against tuberculosis (TB), particularly the Mycobacterium tuberculosis (Mtb) Beijing strain infection. Identification of vaccine antigens (Ags) by considering Mtb genetic diversity is crucial for the development of improved TB vaccine. MTBK_20640, a new Beijing genotype-specific proline-glutamic acid-family Ag, was identified by comparative genomic analysis. Its immunologic features were characterized by evaluating interactions with dendritic cells (DCs), and immunogenicity and vaccine efficacy were determined against highly virulent Mtb Beijing outbreak Korean Beijing (K) strain and HN878 strain in murine infection model...
February 12, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Amit Kaushik, Nicole C Ammerman, Sandeep Tyagi, Vikram Saini, Iwan Vervoort, Sophie Lachau-Durand, Eric Nuermberger, Koen Andries
The potent anti-tuberculosis activity and long half-life of bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: untreated negative control; positive controls of daily rifampin (10 mg/kg), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI bedaquiline at 160 mg/dose (BLAI-160 ); and test regimens of daily bedaquiline at 2...
February 11, 2019: Antimicrobial Agents and Chemotherapy
Katherine Schultheis, Hubert Schaefer, Holly M Pugh, Bryan S Yung, Janet Oh, Jacklyn Nguyen, Laurent Humeau, Kate E Broderick, Trevor R F Smith
The guinea pig has played a pivotal role as a relevant small animal model in the development of vaccines for infectious diseases such as tuberculosis, influenza, diphtheria, and viral hemorrhagic fevers. We have demonstrated that plasmid-DNA (pDNA) vaccine delivery into the skin elicits robust humoral responses in the guinea pig. However, the use of this animal to model immune responses was somewhat limited in the past due to the lack of available reagents and protocols to study T cell responses. T cells play a pivotal role in both immunoprophylactic and immunotherapeutic mechanisms...
January 20, 2019: Journal of Visualized Experiments: JoVE
Heather M Robison, Patricio Escalante, Enrique Valera, Courtney L Erskine, Loretta Auvil, Humberto C Sasieta, Colleen Bushell, Michael Welge, Ryan C Bailey
Latent tuberculosis infection (LTBI) is estimated in nearly one quarter of the world's population, and of those immunocompetent and infected ~10% will proceed to active tuberculosis (TB). Current diagnostics cannot definitively identify LTBI and provide no insight into reactivation risk, thereby defining an unmet diagnostic challenge of incredible global significance. We introduce a new machine-learning-driven approach to LTBI diagnostics that leverages a high throughput, multiplexed cytokine detection technology and powerful bioinformatics to reveal multi-marker signatures for LTBI diagnosis and risk stratification...
February 4, 2019: Integrative Biology: Quantitative Biosciences From Nano to Macro
Erik Nieto-Patlán, Jeanet Serafín-López, Isabel Wong-Baeza, Sonia M Pérez-Tapia, Laura Cobos-Marín, Sergio Estrada-Parra, Iris Estrada-García, Alma D Chávez-Blanco, Rommel Chacón-Salinas
Tuberculosis is one of the leading causes of mortality worldwide, it is caused by Mycobacterium tuberculosis (Mtb), a bacteria that employs several strategies to evade the host immune response. For instance, Mtb interferes with the overexpression of class II transactivator (CIITA) in macrophages exposed to IFN-γ by inhibiting histone acetylation at its promoter, which can be reverted by the histone deacetylase inhibitor (HDACi) sodium butyrate. In this work, we evaluated whether a different HDACi, valproic acid (VPA), could revert the inhibition of gene expression induced by Mtb...
January 2019: Tuberculosis
Markus J T Ojanen, Meri I E Uusi-Mäkelä, Sanna-Kaisa E Harjula, Anni K Saralahti, Kaisa E Oksanen, Niklas Kähkönen, Juha A E Määttä, Vesa P Hytönen, Marko Pesu, Mika Rämet
Tuberculosis is a multifactorial bacterial disease, which can be modeled in the zebrafish (Danio rerio). Abdominal cavity infection with Mycobacterium marinum, a close relative of Mycobacterium tuberculosis, leads to a granulomatous disease in adult zebrafish, which replicates the different phases of human tuberculosis, including primary infection, latency and spontaneous reactivation. Here, we have carried out a transcriptional analysis of zebrafish challenged with low-dose of M. marinum, and identified intelectin 3 (itln3) among the highly up-regulated genes...
January 30, 2019: Scientific Reports
Arjan van Laarhoven, Sofiati Dian, Suzanne van Dorp, Feby Purnama, Valerie A C M Koeken, Emira Diandini, Fitria Utami, Resvi Livia, Lika Apriani, Edwin Ardiansyah, Rob Ter Horst, Mihai G Netea, Tri Hanggono Achmad, Philip C Hill, Rovina Ruslami, Bachti Alisjahbana, James E Ussher, Agnes Indrati, Ayesha Verrall, Ahmad Rizal Ganiem, Reinout van Crevel
Immunopathology contributes to high mortality in tuberculous meningitis (TBM) but little is known about the blood and cerebrospinal fluid (CSF) immune response. We prospectively characterised the immune response of 160 TBM suspects in an Indonesian cohort, including 67 HIV-negative probable or definite TBM cases. TBM patients presented with severe disease and 38% died in 6 months. Blood from TBM patients analysed by flow cytometry showed lower αβT and γδT cells, NK cells and MAIT cells compared to 26 pulmonary tuberculosis patients (2...
January 29, 2019: Scientific Reports
Ofer N Gofrit, Herve Bercovier, Benjamin Y Klein, Irun R Cohen, Tamir Ben-Hur, Charles L Greenblatt
Alzheimer's disease (AD) is a neurodegenerative disorder which is the most prevalent cause of dementia in the western world. Currently, it is the most expensive disease in America, costing more than heart diseases and cancer and as the world population is getting older it is expected to become the most expensive medical disorder in the world. AD is characterized by three core pathologies: accumulation of amyloid β (Aβ) plaques, neurofibrillary tangles (NFT) and sustained inflammation. It is now believed that inflammation provides the link between Aβ and NFT...
February 2019: Medical Hypotheses
Keertan Dheda, Laura Lenders, Shashikant Srivastava, Gesham Magombedze, Helen Wainwright, Prithvi Raj, Stephen J Bush, Gabriele Pollara, Rachelle Steyn, Malika Davids, Anil Pooran, Timothy Pennel, Anthony Linegar, Ruth McNerney, Loven Moodley, Jotam G Pasipanodya, Carolin T Turner, Mahdad Noursadeghi, Robin M Warren, Edward Wakeland, Tawanda Gumbo
RATIONALE: There is poor understanding about protective immunity and the pathogenesis of cavitation in tuberculosis patients. OBJECTIVES: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity. METHODS: Biopsies were obtained from eight pre-determined locations within lung cavities of multidrug-resistant tuberculosis patients undergoing therapeutic surgical resection (n=14) and healthy lung tissue from non-tuberculosis controls (n=10)...
January 29, 2019: American Journal of Respiratory and Critical Care Medicine
Molly A Matty, Daphne R Knudsen, Eric M Walton, Rebecca W Beerman, Mark R Cronan, Charlie J Pyle, Rafael E Hernandez, David M Tobin
Mycobacterium tuberculosis is the leading worldwide cause of death due to a single infectious agent. Existing anti-tuberculous therapies require long treatments and are complicated by multi-drug-resistant strains. Host-directed therapies have been proposed as an orthogonal approach, but few have moved into clinical trials. Here, we use the zebrafish- Mycobacterium marinum infection model as a whole-animal screening platform to identify FDA-approved, host-directed compounds. We identify multiple compounds that modulate host immunity to limit mycobacterial disease, including the inexpensive, safe, and widely used drug clemastine...
January 29, 2019: ELife
Dóra Révész, Ellen G Engelhardt, Johannes J Tamminga, Franz M N H Schramel, Bregje D Onwuteaka-Philipsen, Ewoudt M W van de Garde, Ewout W Steyerberg, Henrica C W de Vet, Veerle M H Coupé
Treatment decision-making for patients with incurable non-small cell lung cancer (NSCLC) is complex due to the rapidly increasing number of treatments and discovery of new biomarkers. Decision support systems (DSS) could assist thoracic oncologists (TO) weighing of the pros and cons of treatments in order to arrive at an evidence-based and personalized treatment advice. Our aim is to inventory (1) TO's needs with regard to DSS in the treatment of incurable (stage IIIB/IV) NSCLC patients, and (2) preferences regarding the development of future tools in this field...
January 26, 2019: Journal of Cancer Education: the Official Journal of the American Association for Cancer Education
Kavita Rawat, Swetarka Das, Budai S Vivek Vinod, Umeshkumar Vekariya, Tanu Garg, Arunava Dasgupta, Raj Kamal Tripathi
AIMS: β casein fragment peptide (54-59) downregulates Basic Transcription factor 3a (BTF3a) in macrophages and exhibits enhanced clearance of M. bovis BCG and several other intracellular pathogens. However, the direct effect of BTF3a downregulation on Mycobacterium tuberculosis (Mtb) survival and the probable pathways involved have not yet been studied. Therefore, the present study was undertaken to deduce the antimycobacterial significance of BTF3a in human macrophages. MAIN METHODS: CRISPR/Cas 9 gRNA was designed to downregulate BTF3a in THP1 derived macrophages...
January 23, 2019: Life Sciences
Yong Cheng, Jeffery S Schorey
Extracellular vesicles (EVs) have been shown to carry microbial components and function in the host defense against infections. In this study, we demonstrate that Mycobacterium tuberculosis ( M.tb ) RNA is delivered into macrophage-derived EVs through an M.tb SecA2-dependent pathway and that EVs released from M.tb -infected macrophages stimulate a host RIG-I/MAVS/TBK1/IRF3 RNA sensing pathway, leading to type I interferon production in recipient cells. These EVs also promote, in a RIG-I/MAVS-dependent manner, the maturation of M...
January 25, 2019: EMBO Reports
Juan Manuel Coya, Laura De Matteis, Alexandre Giraud-Gatineau, Anne Biton, Inés Serrano-Sevilla, Anne Danckaert, Marie-Agnès Dillies, Brigitte Gicquel, Jesus M De la Fuente, Ludovic Tailleux
BACKGROUND: Infectious diseases are still a leading cause of death and, with the emergence of drug resistance, pose a great threat to human health. New drugs and strategies are thus urgently needed to improve treatment efficacy and limit drug-associated side effects. Nanotechnology-based drug delivery systems are promising approaches, offering hope in the fight against drug resistant bacteria. However, how nanocarriers influence the response of innate immune cells to bacterial infection is mostly unknown...
January 25, 2019: Journal of Nanobiotechnology
James S Molton, Benjamin A Thomas, Yan Pang, Lih Kin Khor, James Hallinan, Claire M Naftalin, John J Totman, David W Townsend, Tow Keang Lim, Cynthia Bin Eng Chee, Yee Tang Wang, Nicholas I Paton
BACKGROUND: The understanding of early events following TB exposure is limited by traditional tests that rely on detection of an immune response to infection, which is delayed, or on imaging tests with low sensitivity for early disease. We investigated for evidence of lung abnormalities in heavily exposed TB contacts using PET/MRI. METHODS: 30 household contacts of 20 index patients underwent clinical assessment, IGRA testing, chest x-ray and PET/MRI scan using 18-F-FDG...
January 24, 2019: BMC Infectious Diseases
Tarun K Upadhyay, Nida Fatima, Akanksha Sharma, Deepak Sharma, Rolee Sharma
Recently, yeast-derived glucan particles (GP) have emerged as novel drug delivery agents that provide for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors. In our previous study, we prepared GP loaded with high payload (40.5 + 1.9%) of rifabutin (RB) nano-particles [(RB-NPs)-GP]. We investigated the anti-mycobacterial efficacy and cellular activation responses within Mycobacterium tuberculosis (M. tuberculosis) infected J774 macrophage cells following exposure to the (RB-NPs)-GP formulation...
December 2019: Artificial Cells, Nanomedicine, and Biotechnology
Elena Denisenko, Reto Guler, Musa Mhlanga, Harukazu Suzuki, Frank Brombacher, Sebastian Schmeier
BACKGROUND: Tuberculosis is a life-threatening infectious disease caused by Mycobacterium tuberculosis (M.tb). M.tb subverts host immune responses to build a favourable niche and survive inside of host macrophages. Macrophages can control or eliminate the infection, if acquire appropriate functional phenotypes. Transcriptional regulation is a key process that governs the activation and maintenance of these phenotypes. Among the factors orchestrating transcriptional regulation during M...
January 22, 2019: BMC Genomics
Karin Dijkman, Claudia C Sombroek, Richard A W Vervenne, Sam O Hofman, Charelle Boot, Edmond J Remarque, Clemens H M Kocken, Tom H M Ottenhoff, Ivanela Kondova, Mohammed A Khayum, Krista G Haanstra, Michel P M Vierboom, Frank A W Verreck
Tuberculosis (TB) remains the deadliest infectious disease1 , and the widely used Bacillus Calmette-Guérin (BCG) vaccine fails to curb the epidemic. An improved vaccination strategy could provide a cost-effective intervention to break the transmission cycle and prevent antimicrobial resistance2,3 . Limited knowledge of the host responses critically involved in protective immunity hampers the development of improved TB vaccination regimens. Therefore, assessment of new strategies in preclinical models to select the best candidate vaccines before clinical vaccine testing remains indispensable...
January 21, 2019: Nature Medicine
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