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Mycobacterium Pathogenesis

Neha Agrawal, Ioana Streata, Gang Pei, January Weiner, Leigh Kotze, Silke Bandermann, Laura Lozza, Gerhard Walzl, Nelita du Plessis, Mihai Ioana, Stefan H E Kaufmann, Anca Dorhoi
Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis ( Mtb ) and their impact on granulomas remain undefined...
2018: Frontiers in Immunology
Xiaoling Gao, Cong Wu, Xiaoxia Wang, Hui Xu, Yu Wu, Yonghong Li, Yanjuan Jia, Chaojun Wei, Wenhua He, Yongxiang Wang, Benzhong Zhang
There is an urgent need to identify the potential risk factors for activating latent Mycobacterium tuberculosis infection. In this study, we evaluated the immune function of Rv1737c, which is a latency-associated antigen of dormancy survival regulator (DosR) of M. tuberculosis in a mouse model. Our data showed that mice pretreated with recombinant Rv1737c (rRv1737c) exhibited higher levels of antigen-specific antibodies (IgG, IgM and IgA) than sham-treated mice. Following Bacilli Calmette-Guerin (BCG) challenge, rRv1737c adjuvanted with cholera toxin subunit B (CTB) induced diffuse lung inflammation and fibrosis compared to the control mice...
October 29, 2018: Scandinavian Journal of Immunology
Julio Caballero, Alejandro Morales-Bayuelo, Carlos Navarro-Retamal
In the last decades, human protein kinases (PKs) have been relevant as targets in the development of novel therapies against many diseases, but the study of Mycobacterium tuberculosis PKs (MTPKs) involved in tuberculosis pathogenesis began much later and has not yet reached an advanced stage of development. To increase knowledge of these enzymes, in this work we studied the structural features of MTPKs, with focus on their ATP-binding sites and their interactions with inhibitors. PknA, PknB, and PknG are the most studied MTPKs, which were previously crystallized; ATP-competitive inhibitors have been designed against them in the last decade...
October 26, 2018: Journal of Computer-aided Molecular Design
Xuan Peng, Tao Luo, Xiaoqian Zhai, Chunxi Zhang, Jing Suo, Pengjiao Ma, Chuhan Wang, Lang Bao
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains a serious global health problem. The PE/PPE family, featuring unique sequences, structures and expression in Mtb, is reported to interfere with the macrophage response to the pathogen and facilitate its infection. PPE11 (Rv0453) existed in pathogenic mycobacteria and was persistently expressed in the infected guinea pig lungs. However, the role it played in the pathogenesis remains unclear. Here, to investigate the interaction and potential mechanism of PPE11 between pathogens and hosts, we heterologously expressed PPE11 in non-pathogenic, rapidly growing Mycobacterium smegmatis strains...
October 23, 2018: Microbial Pathogenesis
Anjali Garg, Bandana Kumari, Neelja Singhal, Manish Kumar
Several microbial pathogens cause autoimmune diseases in humans by exhibiting molecular mimicry with the host proteins. However, the contribution of autoimmunity in microbial pathogenesis has not been evaluated critically. Clinical and experimental observations have supported and corroborated that autoimmunity was a fundamental process underlying pathology of human tuberculosis bacteria. In the current review, we propose novel drug targets based on a pathogen's molecular-mimicry-inducing proteins. The process for identification of drug targets has been explained using Mycobacterium tuberculosis as a model organism...
October 23, 2018: Drug Discovery Today
Brian A Norris, Joel D Ernst
Mycobacterium tuberculosis causes chronic infection of mononuclear phagocytes, especially resident (alveolar) macrophages, recruited macrophages, and dendritic cells. Despite the importance of these cells in tuberculosis (TB) pathogenesis and immunity, little is known about the population dynamics of these cells at the sites of infection. We used a combination of congenic monocyte adoptive transfer, and pulse-chase labeling of DNA, to determine the kinetics and characteristics of trafficking, differentiation, and infection of mononuclear phagocytes during the chronic, adaptive immune phase of M...
October 2018: PLoS Pathogens
Sudhanshu Abhishek, Uma Nahar Saikia, Amod Gupta, Reema Bansal, Vishali Gupta, Nirbhai Singh, Suman Laal, Indu Verma
Background: Intraocular tuberculosis (IOTB), an extrapulmonary manifestation of tuberculosis of the eye, has unique and varied clinical presentations with poorly understood pathogenesis. As it is a significant cause of inflammation and visual morbidity, particularly in TB endemic countries, it is essential to study the pathogenesis of IOTB. Clinical and histopathologic studies suggest the presence of Mycobacterium tuberculosis in retinal pigment epithelium (RPE) cells. Methods: A human retinal pigment epithelium (ARPE-19) cell line was infected with a virulent strain of M...
2018: Frontiers in Cellular and Infection Microbiology
Flavia Squeglia, Alessia Ruggiero, Rita Berisio
The scenario of chemical reactions prompted by the infection by Mycobacterium tuberculosis is huge. The infection generates a localized inflammatory response, with the recruitment of neutrophils, monocytes, and T-lymphocytes. Consequences of this immune reaction can be the eradication or containment of the infection, but these events can be deleterious to the host inasmuch as lung tissue can be destroyed. Indeed, a hallmark of tuberculosis (TB) is the formation of lung cavities, which increase disease development and transmission, as they are sites of high mycobacterial burden...
October 11, 2018: Biochemical Journal
Nguyen T T Thuong, Dao N Vinh, Hoang T Hai, Do D A Thu, Le T H Nhat, Dorothee Heemskerk, Nguyen D Bang, Maxine Caws, Nguyen T H Mai, Guy E Thwaites
Background: Mycobacterium tuberculosis (Mtb) bacillary load in the brain of those with tuberculous meningitis (TBM) may reflect the host ability to control the pathogen and determine disease severity and treatment outcomes. Methods: We measured pre-treatment cerebrospinal fluid (CSF) Mtb bacterial load by GeneXpert in 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes...
October 9, 2018: Journal of Infectious Diseases
Seon-Hwa Kim, Soo-Na Cho, Yun-Ji Lim, Ji-Ae Choi, Junghwan Lee, Dam Go, Chang-Hwa Song
Background: Mycobacterium smegmatis , a rapidly growing non-tuberculosis mycobacterium, is a good model for studying the pathogenesis of tuberculosis because of its genetic similarity to Mycobacterium tuberculosis (Mtb). Macrophages remove mycobacteria during an infection. Macrophage apoptosis is a host defense mechanism against intracellular bacteria. We have reported that endoplasmic reticulum (ER) stress is an important host defense mechanism against Mtb infection. Results: In this study, we found that M...
2018: Cell & Bioscience
Amira Refai, Sami Gritli, Mohamed-Ridha Barbouche, Makram Essafi
Tuberculosis, a human infectious disease caused by Mycobacterium tuberculosis ( M.tb ), is still a major cause of morbidity and mortality worldwide. The success of M.tb as a pathogen relies mainly on its ability to divert the host innate immune responses. One way by which M.tb maintains a persistent infection in a "silent" granuloma is to inhibit inflammation and induce an immunoregulatory phenotype in host macrophages (MΦs). However, M.tb effectors governing the switch of MΦs from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype remain to be determined...
2018: Frontiers in Cellular and Infection Microbiology
Robert L Hunter
It has long been recognized that tuberculosis (TB) induces both protective and tissue damaging immune responses. This paper reviews nearly two centuries of evidence that protection and tissue damage are mediated by separate disease entities in humans. Primary TB mediates protective immunity to disseminated infection while post-primary TB causes tissue damage that results in formation of cavities. Both are necessary for continued survival of Mycobacterium tuberculosis (MTB). Primary TB has been extensively studied in humans and animals...
2018: Frontiers in Immunology
Nadya Rakovitsky, Michal Bar Oz, Karin Goldberg, Simon Gibbons, Oren Zimhony, Daniel Barkan
Nitrogen metabolism plays a central role in the physiology of microorganisms, and Glutamine Synthetase (GS) genes are present in virtually all bacteria. In M. tuberculosis , four GS genes are present, but only glnA1 is essential, whereas glnA2 was shown to be non-essential for in-vitro as well as in-vivo growth and pathogenesis, and is postulated to be involved in D-glutamine and iso-glutamine synthesis. Whilst investigating the activity of an antimicrobial compound in M. smegmatis , we found a spontaneous temperature-sensitive mutant in glnA2 (I133F), and used it to investigate the role of glnA2 in M...
2018: Frontiers in Microbiology
Jun Sun, Ling-Li Yang, Xi Chen, De-Xin Kong, Rong Liu
Tuberculosis (TB) is one of the biggest infectious disease killers caused by Mycobacterium tuberculosis (MTB). Studying the protein-protein interactions (PPIs) between MTB and human can deepen our understanding of the pathogenesis of TB and offer new clues to the treatment against MTB infection, but the experimentally validated interactions are especially scarce in this regard. Herein we proposed an integrated framework that combined template-, domain-domain interaction-, and machine learning-based methods to predict MTB-human PPIs...
November 2, 2018: Journal of Proteome Research
Kimberly M Davis, Ralph R Isberg
It has been known for decades that individual cells within pathogenic bacterial populations have reduced antibiotic susceptibility, which is linked to decreased metabolic rates. A similar phenomenon occurs with virulence-associated proteins, as reduced expression is associated with increased fitness of individual cells. Non-producers within the population can benefit from the virulence proteins produced by others in the population without suffering a fitness cost, thus maintaining a genetically uniform population...
September 19, 2018: Trends in Microbiology
Nina T Odermatt, Claudia Sala, Andrej Benjak, Stewart T Cole
Tight control of gene expression is crucial for Mycobacterium tuberculosis to adapt to the changing environments encountered when infecting or exiting human cells. While three nucleoid associated proteins (NAPs) EspR, HupB and Lsr2 have been investigated, the role of a fourth, the mycobacterial integration host factor (mIHF), remains elusive. Here, we report a multidisciplinary functional analysis that exploits a conditional mIHF mutant. Gene silencing was bactericidal and resulted in elongated cells devoid of septa, with only one nucleoid...
September 21, 2018: Scientific Reports
Jing Yao, Xingran Du, Sixia Chen, Yan Shao, Kaili Deng, Mingzi Jiang, Jingning Liu, Ziyan Shen, Xiaolin Chen, Ganzhu Feng
The intracellular survival of Mycobacterium tuberculosis (Mtb) has a central role in the pathogenesis of tuberculosis. Mtb Rv2346c is a member of 6-kDa early secreted antigenic target family of proteins, which are known to inhibit the host immune responses to promote bacillary persistence in macrophages. However, the mechanism through which Rv2346c participates in Mtb pathogenesis is unclear. In the present study, recombinant Rv2346c protein was synthesized and used to treat Bacillus Calmette-Guérin (BCG)-infected macrophages...
September 19, 2018: Emerging Microbes & Infections
Sivaranjani Namasivayam, Alan Sher, Michael S Glickman, Matthew F Wipperman
Tuberculosis (TB) is an ancient infectious disease of humans that has been extensively studied both clinically and experimentally. Although susceptibility to Mycobacterium tuberculosis infection is clearly influenced by factors such as nutrition, immune status, and both mycobacterial and host genetics, the variable pathogenesis of TB in infected individuals remains poorly understood. During the past two decades, it has become clear that the microbiota-the trillion organisms that reside at mucosal surfaces within and on the body-can exert a major influence on disease outcome through its effects on host innate and adaptive immune function and metabolism...
September 18, 2018: MBio
Matt D Johansen, Elinor Hortle, Joshua A Kasparian, Alejandro Romero, Beatriz Novoa, Antonio Figueras, Warwick J Britton, Kumudika de Silva, Auriol C Purdie, Stefan H Oehlers
Changes to lipid metabolism are well-characterised consequences of human tuberculosis infection but their functional relevance are not clearly elucidated in these or other host-mycobacterial systems. The zebrafish-Mycobacterium marinum infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of infection-induced lipid metabolism. We find mammalian mycobacterial infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of mycobacterial pathogenesis...
September 13, 2018: Fish & Shellfish Immunology
Flavio De Maio, Basem Battah, Valentina Palmieri, Linda Petrone, Francesco Corrente, Alessandro Salustri, Ivana Palucci, Silvia Bellesi, Massimiliano Papi, Salvatore Rubino, Michela Sali, Delia Goletti, Maurizio Sanguinetti, Riccardo Manganelli, Marco De Spirito, Giovanni Delogu
PE_PGRSs of Mycobacterium tuberculosis (Mtb) represent a family of complex and peculiar proteins whose role and function remain elusive. In this study, we investigated PE_PGRS3 and PE_PGRS4, two highly homologous PE_PGRSs encoded by two contiguous genes in the Mtb genome. Using a gene-reporter system in Mycobacterium smegmatis (Ms) and transcriptional analysis in Mtb, we show that PE_PGRS3, but not PE_PGRS4, is specifically expressed under low phosphate concentrations. Interestingly, PE_PGRS3, but not PE_PGRS4, has a unique, arginine-rich C-terminal domain of unknown function...
September 7, 2018: Cellular Microbiology
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