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https://www.readbyqxmd.com/read/29330469/mycobacterium-tuberculosis-exploits-a-molecular-off-switch-of-the-immune-system-for-intracellular-survival
#1
Ulrich von Both, Maurice Berk, Paul-Michael Agapow, Joseph D Wright, Anna Git, Melissa Shea Hamilton, Greg Goldgof, Nazneen Siddiqui, Evangelos Bellos, Victoria J Wright, Lachlan J Coin, Sandra M Newton, Michael Levin
Mycobacterium tuberculosis (M. tuberculosis) survives and multiplies inside human macrophages by subversion of immune mechanisms. Although these immune evasion strategies are well characterised functionally, the underlying molecular mechanisms are poorly understood. Here we show that during infection of human whole blood with M. tuberculosis, host gene transcriptional suppression, rather than activation, is the predominant response. Spatial, temporal and functional characterisation of repressed genes revealed their involvement in pathogen sensing and phagocytosis, degradation within the phagolysosome and antigen processing and presentation...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29325545/phthiocerol-dimycocerosates-promote-access-to-the-cytosol-and-intracellular-burden-of-mycobacterium-tuberculosis-in-lymphatic-endothelial-cells
#2
Thomas R Lerner, Christophe J Queval, Antony Fearns, Urska Repnik, Gareth Griffiths, Maximiliano G Gutierrez
BACKGROUND: Phthiocerol dimycocerosates (PDIM), glycolipids found on the outer surface of virulent members of the Mycobacterium tuberculosis (Mtb) complex, are a major contributing factor to the pathogenesis of Mtb. Myelocytic cells, such as macrophages and dendritic cells, are the primary hosts for Mtb after infection and previous studies have shown multiple roles for PDIM in supporting Mtb in these cells. However, Mtb can infect other cell types. We previously showed that Mtb efficiently replicates in human lymphatic endothelial cells (hLECs) and that the hLEC cytosol acts as a reservoir for Mtb in humans...
January 4, 2018: BMC Biology
https://www.readbyqxmd.com/read/29324800/hepcidin-deficiency-and-iron-deficiency-do-not-alter-tuberculosis-susceptibility-in-a-murine-m-tb-infection-model
#3
Rachel Harrington-Kandt, Elena Stylianou, Lucy A Eddowes, Pei Jin Lim, Lisa Stockdale, Nawamin Pinpathomrat, Naomi Bull, Janet Pasricha, Marta Ulaszewska, Yulia Beglov, Sophie Vaulont, Hal Drakesmith, Helen McShane
Tuberculosis (TB), caused by the macrophage-tropic pathogen Mycobacterium tuberculosis (M.tb) is a highly prevalent infectious disease. Since an immune correlate of protection or effective vaccine have yet to be found, continued research into host-pathogen interactions is important. Previous literature reports links between host iron status and disease outcome for many infections, including TB. For some extracellular bacteria, the iron regulatory hormone hepcidin is essential for protection against infection...
2018: PloS One
https://www.readbyqxmd.com/read/29319347/sigma-factors-mediated-signaling-in-mycobacterium-tuberculosis
#4
Peifu Zhou, Xinpeng Wang, Yuzhong Zhao, Wei Yuan, Jianping Xie
Activation of signaling cascades is critical for Mycobacterium tuberculosis (Mtb) to adapt the macrophage lifestyle. Parallel to several signal systems, sigma factor systems, especially the extra-cytoplasmic function sigma factors, are crucial for Mtb signaling. Most sigma factors lack a signal sensory domain and often are activated by various proteins that perceive the environmental cues and relay the signals through variegated post-translational modifications via the activity of antisigma factor, protein kinase and related transcriptional regulators...
January 10, 2018: Future Microbiology
https://www.readbyqxmd.com/read/29317718/protein-tyrosine-kinase-ptka-is-required-for-mycobacterium-tuberculosis-growth-in-macrophages
#5
Dennis Wong, Wu Li, Joseph D Chao, Peifu Zhou, Gagandeep Narula, Clement Tsui, Mary Ko, Jianping Xie, Carlos Martinez-Frailes, Yossef Av-Gay
Protein phosphorylation plays a key role in Mycobacterium tuberculosis (Mtb) physiology and pathogenesis. We have previously shown that a secreted protein tyrosine phosphatase, PtpA, is essential for Mtb inhibition of host macrophage acidification and maturation, and is a substrate of the protein tyrosine kinase, PtkA, encoded in the same operon. In this study, we constructed a ∆ptkA deletion mutant in Mtb and found that the mutant exhibited impaired intracellular survival in the THP-1 macrophage infection model, correlated with the strain's inability to inhibit macrophage phagosome acidification...
January 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29311492/innate-immunity-mediated-by-dendritic-cells-macrophages-plays-a-central-role-in-the-early-period-in-tumor-treatment-using-gene-of-mycobacterium-tuberculosis-antigen
#6
Takahiro Ushigusa, Yoshiyuki Koyama, Tomoko Ito, Kenichi Watanabe, James K Chambers, Aya Hasegawa, Kazuyuki Uchida, Ryoji Kanegi, Shingo Hatoya, Toshio Inaba, Kikuya Sugiura
By using a complex of DNA, polyethylenimine and chondroitin sulfate, the in vivo transfection of early secretory antigenic target-6 (ESAT-6) gene into tumor cells was found to cause significant suppression of the tumor growth. In order to apply the method in clinical cancer treatment in dogs and cats, mechanisms underlying the suppressive effects were investigated in a tumor-bearing mouse model. The transfection efficiency was only about 10%, but the transfection of ESAT-6 DNA nevertheless induced systemic immune responses against ESAT-6...
January 1, 2018: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/29311080/mycobacterium-abscessus-smooth-and-rough-morpohotypes-form-antimicrobial-tolerant-biofilm-phenotypes-but-are-killed-by-acetic-acid
#7
Gillian Clary, Smitha Sasindran, Nathan Nesbitt, Laurel Mason, Sara Cole, Abul Azad, Karen McCoy, Larry S Schlesinger, Luanne Hall-Stoodley
Mycobacterium abscessus has emerged as an important pathogen in people with chronic inflammatory lung diseases such as cystic fibrosis, and recent reports suggest that it may be transmissible by fomites. M. abscessus exhibits two major colony morphology variants: a smooth morphotype (MaSm ) and a rough morphotype (MaRg ). Biofilm formation, prolonged intracellular survival, and colony variant diversity can each contribute to the persistence of M. abscessus and other bacterial pathogens in chronic pulmonary diseases...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29301937/cyclipostins-and-cyclophostin-analogs-inhibit-the-antigen-85c-from-mycobacterium-tuberculosis-both-in-vitro-and-in-vivo
#8
Albertus Viljoen, Matthias Richard, Phuong Chi Nguyen, Patrick Fourquet, Luc Camoin, Rishi R Paudal, Giri R Gnawali, Christopher D Spilling, Jean-François Cavalier, Stéphane Canaan, Mickael Blaise, Laurent Kremer
An increasing prevalence of cases of drug-resistant tuberculosis requires the development of more efficacious chemotherapies. We previously reported the discovery of a new class of Cyclipostins and Cyclophostin (CyC) analogs exhibiting potent activity against Mycobacterium tuberculosis both in vitro and in infected macrophages. Competitive labeling/enrichment assays combined with MS have identified several serine or cysteine enzymes in lipid and cell wall metabolism as putative targets of these CyC compounds...
January 4, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29300790/correction-alternate-splicing-of-transcripts-shape-macrophage-response-to-mycobacterium-tuberculosis-infection
#9
Haroon Kalam, Mary F Fontana, Dhiraj Kumar
[This corrects the article DOI: 10.1371/journal.ppat.1006236.].
January 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29283461/a-pathway-based-association-analysis-identified-fmnl1-map3k14-as-susceptibility-genes-for-leprosy
#10
Huimin Zhang, Zhenzhen Wang, Xi'an Fu, Yonghu Sun, Zihao Mi, Gongqi Yu, Lele Sun, Na Wang, Chuan Wang, Qing Zhao, Qing Pan, Zhenhua Yue, Hong Liu, Furen Zhang
The nuclear transcription factor-κB (NF-κB) plays a pivotal role in controlling both innate and adaptive immunity and regulates the expressions of many immunological mediators. Abundant evidences have showed that the importance of NF-κB pathway in the host immune responses against Mycobacterium leprae in the development of leprosy. However, no particular association study between leprosy and NF-κB pathway related gene polymorphisms was reported. Here, we performed a large scale and two-stage candidate association study to investigate the association between 94 NF-κB pathway related genes and leprosy...
December 28, 2017: Experimental Dermatology
https://www.readbyqxmd.com/read/29275228/naturally-occurring-diels-alder-type-adducts-from-morus-nigra-as-potent-inhibitors-of-mycobacterium-tuberculosis-protein-tyrosine-phosphatase-b
#11
Alessandra Mascarello, Angela Camila Orbem Menegatti, Andrea Calcaterra, Priscila Graziela Alves Martins, Louise Domeneghini Chiaradia-Delatorre, Ilaria D'Acquarica, Franco Ferrari, Valentina Pau, Adriana Sanna, Alessandro De Logu, Maurizio Botta, Bruno Botta, Hernán Terenzi, Mattia Mori
Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatases A and B (PtpA and PtpB) have been recognized as potential molecular targets for the development of new therapeutic strategies against tuberculosis (TB). In this context, we have recently reported that the naturally occurring Diels-Alder-type adduct Kuwanol E is an inhibitor of PtpB (Ki = 1.6 ± 0.1 μM). Here, we describe additional Diels-Alder-type adducts isolated from Morus nigra roots bark that inhibit PtpB at sub-micromolar concentrations...
December 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29259583/inhibition-of-tissue-matrix-metalloproteinases-interferes-with-mycobacterium-tuberculosis-induced-granuloma-formation-and-reduces-bacterial-load-in-a-human-lung-tissue-model
#12
Venkata R Parasa, Jagadeeswara R Muvva, Jeronimo F Rose, Clara Braian, Susanna Brighenti, Maria Lerm
Granulomas are hallmarks of pulmonary tuberculosis (TB) and traditionally viewed as host-protective structures. However, recent evidence suggest that Mycobacterium tuberculosis (Mtb) uses its virulence factors to stimulate the formation of granuloma. In the present study, we investigated the contribution of matrix metalloproteinases (MMPs), host enzymes that cause degradation of the extracellular matrix, to granuloma formation and bacterial load in Mtb-infected tissue. To this end, we used our lung tissue model for TB, which is based on human lung-derived cells and primary human monocyte-derived macrophages...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/29251248/the-e3-ubiquitin-ligase-nedd4-enhances-killing-of-membrane-perturbing-intracellular-bacteria-by-promoting-autophagy
#13
Gang Pei, Hellen Buijze, Haipeng Liu, Pedro Moura-Alves, Christian Goosmann, Volker Brinkmann, Hiroshi Kawabe, Anca Dorhoi, Stefan H E Kaufmann
The E3 ubiquitin ligase NEDD4 has been intensively studied in processes involved in viral infections, such as virus budding. However, little is known about its functions in bacterial infections. Our investigations into the role of NEDD4 in intracellular bacterial infections demonstrate that Mycobacterium tuberculosis and Listeria monocytogenes, but not Mycobacterium bovis BCG, replicate more efficiently in NEDD4 knockdown macrophages. In parallel, NEDD4 knockdown or knockout impaired basal macroautophagy/autophagy, as well as infection-induced autophagy...
December 17, 2017: Autophagy
https://www.readbyqxmd.com/read/29243495/the-recombinant-fusion-protein-cfp10-esat6-difn-has-protective-effect-against-tuberculosis-in-guinea-pigs
#14
Natalya V Permyakova, Pavel A Belavin, Dariya S Pirozhkova, Elena G Ufimtseva, Sergey M Rozov, Sergey R Mursalimov, Yuriy V Sidorchuk, Elena A Uvarova, Alla A Zagorskaya, Tatiana V Marenkova, Svetlana V Bannikova, Evgeniy A Demidov, Konstantin V Starostin, Marionella A Kravchenko, Diana V Vakhrusheva, Roman B Berdnikov, Natalya I Eremeeva, Sergey N Skornyakov, Sergey E Peltek, Elena V Deineko
Development of effective vaccine candidates against tuberculosis (TB) is currently the most important challenge in the prevention of this disease since the BCG vaccine fails to guarantee a lifelong protection, while any other approved vaccine with better efficiency is still absent. The protective effect of the recombinant fusion protein CFP10-ESAT6-dIFN produced in a prokaryotic expression system (Escherichia coli) has been assessed in a guinea pig model of acute TB. The tested antigen comprises the Mycobacterium tuberculosis (Mtb) proteins ESAT6 and CFP10 as well as modified human γ-interferon (dIFN) for boosting the immune response...
December 15, 2017: Acta Microbiologica et Immunologica Hungarica
https://www.readbyqxmd.com/read/29242190/the-rv2633c-protein-of-mycobacterium-tuberculosis-is-a-non-heme-di-iron-catalase-with-a-possible-role-in-defenses-against-oxidative-stress
#15
Zhongxin Ma, Kyle T Strickland, Michelle D Cherne, Esha Sehanobish, Kyle H Rohde, William T Self, Victor L Davidson
The Rv2633c gene in Mycobacterium tuberculosis is rapidly upregulated after macrophage infection, suggesting that Rv2633c is involved in M. tuberculosis pathogenesis. However, the activity and role of the Rv2633c protein in host colonization is unknown. Here, we analyzed the Rv2633c protein sequence, which revealed the presence of an HHE cation-binding domain common in hemerythrin-like proteins. Phylogenetic analysis indicated that Rv2633c is a member of a distinct subset of hemerythrin-like proteins exclusive to mycobacteria...
December 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29239661/enhancement-of-the-antimycobacterial-activity-of-macrophages-by-ajoene
#16
Ji-Ae Choi, Soo-Na Cho, Yun-Ji Lim, Junghwan Lee, Dam Go, Seon-Hwa Kim, Chang-Hwa Song
Ajoene, a garlic-derived sulfur-containing compound, has broad-spectrum antimicrobial activity. To assess the potential of ajoene for treating tuberculosis (TB), we determined whether it induces the stress response of the endoplasmic reticulum (ER), which plays an important role in TB. We showed that ajoene stimulation induced the production of ER stress sensor molecules and reactive oxygen species (ROS) levels. Ajoene-induced ROS production was dependent on c-Jun N-terminal kinase (JNK) activation. Interestingly, the inhibition of JNK activity and suppression of ROS production reduced ajoene-induced CHOP production in macrophages...
January 1, 2017: Innate Immunity
https://www.readbyqxmd.com/read/29236768/autophagy-induction-by-mycobacterium-indicus-pranii-promotes-mycobacterium-tuberculosis-clearance-from-raw-264-7-macrophages
#17
Bindu Singh, Mohd Saqib, Ananya Gupta, Pawan Kumar, Sangeeta Bhaskar
Mycobacterium indicus pranii (MIP) is a potent vaccine candidate against tuberculosis (TB) as it has demonstrated significant protection in animal models of tuberculosis as well as in clinical trials. Higher protective efficacy of MIP against TB as compared to BCG provoked the efforts to gain insight into the molecular mechanisms underlying MIP mediated protection against Mycobacterium tuberculosis (M.tb). Autophagy, initially described as a cell survival mechanism during starvation, also plays a key role in host resistance to M...
2017: PloS One
https://www.readbyqxmd.com/read/29233902/t-cell-production-of-gm-csf-protects-the-host-during-experimental-tuberculosis
#18
Richard T Robinson
Although classically associated with myelopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) is increasingly recognized as being important for tuberculosis (TB) resistance. GM-CSF is expressed by nonhematopoietic and hematopoietic lineages following infection with Mycobacterium tuberculosis and is necessary to restrict M. tuberculosis growth in experimental models. Until the recent study by Rothchild et al. (mBio 8:e01514-17, 2017, https://doi.org/10.1128/mBio.01514-17), it was unknown whether GM-CSF-producing T cells contribute to TB resistance...
December 12, 2017: MBio
https://www.readbyqxmd.com/read/29233822/hematopoietic-stem-cell-gene-therapy-for-ifn%C3%AE-r1-deficiency-protects-mice-from-mycobacterial-infections
#19
Miriam Hetzel, Adele Mucci, Patrick Blank, Ariane Hai Ha Nguyen, Jan Schiller, Olga Halle, Mark-Philipp Kühnel, Sandra Billig, Robert Meineke, Daniel Brand, Vanessa Herder, Wolfgang Baumgärtner, Franz-Christoph Bange, Ralph Goethe, Danny Jonigk, Reinhold Förster, Bernhard Gentner, Jean-Laurent Casanova, Jacinta Bustamante, Axel Schambach, Ulrich Kalinke, Nico Lachmann
Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare primary immunodeficiency, characterized by severe infections caused by weakly virulent mycobacteria. Bi-allelic null mutations in genes encoding interferon gamma (IFNγ) receptor 1 or -2 (IFNGR1, IFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant IFNγ therapy is inefficient and hematopoietic stem cell transplantation (HSCT) has a poor prognosis. Thus, we developed a HSC gene therapy approach using lentiviral vectors expressing Ifnγr1 either constitutively or myeloid-specifically...
December 12, 2017: Blood
https://www.readbyqxmd.com/read/29233104/tlr4-nox2-axis-regulates-the-phagocytosis-and-killing-of-mycobacterium-tuberculosis-by-macrophages
#20
Jingzhu Lv, Xiaoyan He, Hongtao Wang, Zhaohua Wang, Gabriel T Kelly, Xiaojing Wang, Yin Chen, Ting Wang, Zhongqing Qian
BACKGROUND: Macrophages stand at the forefront of both innate and adapted immunity through their capacities to recognize, engulf, and eliminate foreign particles, and to stimulate adapted immune cells. They are also involved in controlling pro- and anti-inflammatory pathways. Macrophage activity against Mycobacterium tuberculosis (M. tuberculosis) has been shown to involve Toll-like receptor (TLR) activation and ROS production. Previous studies have shown that lipopolysaccharide (LPS), through TLR4, could activate macrophages, improve their bactericidal ROS production, and facilitate anti-infective immune responses...
December 12, 2017: BMC Pulmonary Medicine
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