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Pathogenesis AND Tuberculosis

Richard A Slayden, Clinton C Dawson, Jason E Cummings
There has been a significant reduction in annual tuberculosis incidence since the World Health Organization declared tuberculosis a global health threat. However, treatment of M. tuberculosis infections requires lengthy multidrug therapeutic regimens to achieve a durable cure. The development of new drugs that are active against resistant strains and phenotypically diverse organisms continues to present the greatest challenge in the future. Numerous phylogenomic analyses have revealed that the Mtb genome encodes a significantly expanded repertoire of toxin-antitoxin (TA) loci that makes up the Mtb TA system...
June 1, 2018: Pathogens and Disease
Umay Kulsum, Arti Kapil, Harpreet Singh, Punit Kaur
Recent advancements in sequencing technologies have decreased both time span and cost for sequencing the whole bacterial genome. High-throughput Next-Generation Sequencing (NGS) technology has led to the generation of enormous data concerning microbial populations publically available across various repositories. As a consequence, it has become possible to study and compare the genomes of different bacterial strains within a species or genus in terms of evolution, ecology and diversity. Studying the pan-genome provides insights into deciphering microevolution, global composition and diversity in virulence and pathogenesis of a species...
2018: Advances in Experimental Medicine and Biology
Wing Wai Yew, Kwok Chiu Chang, Denise P Chan
Hepatotoxicity induced by antituberculosis drugs is a serious adverse reaction with significant morbidity and even rarely mortality. This form of toxicity potentially impacts the treatment outcome of tuberculosis in some patients. Confining to first-line antituberculosis drugs, this review addresses whether and how oxidative stress, and more broadly, disturbance in redox homeostasis alongside mitochondrial dysfunction, may contribute to the hepatotoxicity induced by them. Risk factors for such toxicity that have been identified, in addition to genetic factors, principally include old age, malnutrition, alcoholism, chronic hepatitis C and chronic hepatitis B infection, HIV infection and pre-existing liver disease...
May 21, 2018: Antimicrobial Agents and Chemotherapy
Jeremy P Huynh, Chih-Chung Lin, Jacqueline M Kimmey, Nicholas N Jarjour, Elizabeth A Schwarzkopf, Tara R Bradstreet, Irina Shchukina, Oleg Shpynov, Casey T Weaver, Reshma Taneja, Maxim N Artyomov, Brian T Edelson, Christina L Stallings
The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis ( Mtb ) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ...
May 17, 2018: Journal of Experimental Medicine
Hyun-Jung Koh, Ye-Ram Kim, Jae-Sung Kim, Jin-Seung Yun, Sojin Kim, Sun Young Kim, Kiseok Jang, Chul-Su Yang
The tumor suppressor gene CD82/KAI1 is a member of the tetraspanin superfamily and organizes various membrane-based processes. Mycobacterium tuberculosis (MTB) persists in host macrophages by interfering with phagolysosome biogenesis and inflammatory responses, but the role of CD82 in controlling the intracellular survival of pathogenic mycobacteria within macrophages remains poorly understood. In this study, we demonstrated that the virulent MTB strain H37Rv (MTB Rv) induced CD82 promoter hypomethylation, resulting in CD82 expression...
May 14, 2018: Experimental & Molecular Medicine
Alvaro A Ordonez, Supriya Pokkali, Sunhwa Kim, Brian Carr, Mariah H Klunk, Leah Tong, Vikram Saini, Yong S Chang, Matthew McKevitt, Victoria Smith, David L Gossage, Sanjay K Jain
Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks...
2018: PloS One
Elizabeth A Ihms, Michael E Urbanowski, William R Bishai
Effacement of normal lung parenchyma by cavities is an important sequela of pulmonary tuberculosis. Despite its clinical significance, the pathogenesis of tuberculous cavitation is poorly understood, with controversy as to whether the fundamental mechanism involves matrix depletion, lipid pneumonia, or mechanical factors. In this study, a repetitive aerosol infection model using Mycobacterium tuberculosis was used to generate cavities in 20 New Zealand White rabbits. Serial computed tomography was performed to monitor cavity progression over 14 weeks...
May 10, 2018: American Journal of Pathology
Handrean Soran, Jan Hoong Ho, Paul N Durrington
PURPOSE OF REVIEW: Acquired hypocholesterolaemia occurs more commonly than inherited hypocholesterolaemia but has received little attention in the literature. In this review, we discuss the causes and underlying mechanisms of acquired hypocholesterolaemia and its relevance to safety of therapeutically induced decreased LDL cholesterol levels. RECENT FINDINGS: Hypocholesterolaemia is increasingly identified as cholesterol testing becomes more widespread in the assessment of cardiovascular risk...
May 8, 2018: Current Opinion in Lipidology
Raquel Vallejo, Juan Francisco García Marín, Ramón Antonio Juste, Marta Muñoz-Mendoza, Francisco Javier Salguero, Ana Balseiro
BACKGROUND: Sheep have been traditionally considered as less susceptible to Mycobacterium bovis (Mbovis) infection than other domestic ruminants such as cattle and goats. However, there is increasing evidence for the role of this species as a domestic Mbovis reservoir, mostly when sheep share grazing fields with infected cattle and goats. Nevertheless, there is a lack of information about the pathogenesis and the immune response of Mbovis infection in sheep. The goals of this study were to characterize the granuloma stages produced by the natural infection of Mbovis in sheep, to compare them with other species and to identify possible differences in the sheep immune response...
May 4, 2018: BMC Veterinary Research
Shamba Gupta, G Marcela Rodriguez
Mycobacteria, like other bacteria, archaea and eukaryotic cells, naturally release extracellular vesicles (EVs) to interact with their environment. EVs produced by pathogenic bacteria are involved in many activities including cell-cell communication, immunomodulation, virulence and cell survival. Although EVs released by thick cell wall microorganisms like mycobacteria were recognized only recently, studies of Mycobacterium tuberculosis EVs already point to their important roles in host pathogen interactions, opening exciting new areas of investigation...
June 1, 2018: Pathogens and Disease
Joanne Turner, Jordi B Torrelles
Mannose-capped lipoarabinomannan (ManLAM), present in all members of the Mycobacterium tuberculosis complex and in other pathogenic Mycobacterium spp, is a high molecular mass amphipathic lipoglycan with a defined critical role in mycobacterial survival during infection. In particular, ManLAM is well-characterized for its importance in providing M. tuberculosis a safe portal of entry to phagocytes, regulating the intracellular trafficking network, as well as immune responses of infected host cells. These ManLAM immunological characteristics are thought to be linked to the subtle but unique and well-defined structural characteristics of this molecule, including but not limited to the degree of acylation, the length of the D-mannan and D-arabinan cores, the length of the mannose caps, as well as the presence of other acidic constituents such as succinates, lactates and/or malates, and also the presence of 5-methylthioxylosyl...
June 1, 2018: Pathogens and Disease
Kaley M Wilburn, Rachael A Fieweger, Brian C VanderVen
Tuberculosis is a distinctive disease in which the causative agent, Mycobacterium tuberculosis, can persist in humans for decades by avoiding clearance from host immunity. During infection, M. tuberculosis maintains viability by extracting and utilizing essential nutrients from the host, and this is a prerequisite for all of the pathogenic activities that are deployed by the bacterium. In particular, M. tuberculosis preferentially acquires and metabolizes host-derived lipids (fatty acids and cholesterol), and the bacterium utilizes these substrates to cause and maintain disease...
March 1, 2018: Pathogens and Disease
Nathan J MacGilvary, Shumin Tan
The pathogenesis of Mycobacterium tuberculosis (Mtb) is intrinsically linked to its intimate and enduring interaction with its host, and understanding Mtb-host interactions at a molecular level is critical to attempts to decrease the significant burden of tuberculosis disease. The marked heterogeneity that exists in lesion progression and outcome during Mtb infection necessitates the development of methods that enable in situ analyses of Mtb biology and host response within the spatial context of tissue structure...
April 1, 2018: Pathogens and Disease
Kathan Mehta, Palashkumar Jaiswal, Farren Briggs, William A Faubion, James H Tabibian, Fabio Cominelli, Maneesh Dave
The impact of underlying immune-mediated inflammatory diseases (IMID) in patients undergoing hematopoietic stem cell transplant (HSCT) is unclear. Hematopoietic cell transplantation co-morbidity index (HCT-CI) is gaining acceptance as a reliable clinical method to score pre-transplant co-morbidities. Higher HCT-CI from a co-morbid IMID implies higher NRM. However, HCT-CI integrates many IMIDs with different pathogenesis and treatment together which may lead to spurious results. We performed a cross-sectional study using Nationwide Inpatient Sample dataset from 1998 to 2011 to compare the outcomes of HSCT in patients with different co-morbid IMIDs with patients without any co-morbid IMIDs...
May 1, 2018: Scientific Reports
Sugata Roy, Sebastian Schmeier, Bogumil Kaczkowski, Erik Arner, Tanvir Alam, Mumin Ozturk, Ousman Tamgue, Suraj P Parihar, Hideya Kawaji, Masayoshi Itoh, Timo Lassmann, Piero Carninci, Yoshihide Hayashizaki, Alistair R R Forrest, Reto Guler, Vladimir B Bajic, Frank Brombacher, Harukazu Suzuki
Mycobacterium tuberculosis (Mtb) infection reveals complex and dynamic host-pathogen interactions, leading to host protection or pathogenesis. Using a unique transcriptome technology (CAGE), we investigated the promoter-based transcriptional landscape of IFNγ (M1) or IL-4/IL-13 (M2) stimulated macrophages during Mtb infection in a time-kinetic manner. Mtb infection widely and drastically altered macrophage-specific gene expression, which is far larger than that of M1 or M2 activations. Gene Ontology enrichment analysis for Mtb-induced differentially expressed genes revealed various terms, related to host-protection and inflammation, enriched in up-regulated genes...
April 30, 2018: Scientific Reports
Katelyn E Zulauf, Jonathan Tabb Sullivan, Miriam Braunstein
To subvert host defenses, Mycobacterium tuberculosis (Mtb) avoids being delivered to degradative phagolysosomes in macrophages by arresting the normal host process of phagosome maturation. Phagosome maturation arrest by Mtb involves multiple effectors and much remains unknown about this important aspect of Mtb pathogenesis. The SecA2 dependent protein export system is required for phagosome maturation arrest and consequently growth of Mtb in macrophages. To better understand the role of the SecA2 pathway in phagosome maturation arrest, we identified two effectors exported by SecA2 that contribute to this process: the phosphatase SapM and the kinase PknG...
April 30, 2018: PLoS Pathogens
M Sevtekin, O Ozmen
We evaluated osteopontin (OPN) and sirtuin-1 (SIRT-1) expression in bovine tuberculosis lesions. The organs of cattle with tuberculosis (TB) were examined for morphology, histopathology and immunohistochemistry of OPN and SIRT-1 expression. Macroscopic lesions commonly were localized in the lungs and mediastinal lymph nodes as well as in livers and hearts. Mycobacterial agents were detected in lesions using the Ziehl-Neelsen method. No OPN or SIRT-1 expression was detected by immunohistochemistry in normal tissues, whereas a marked increase in their expressions was observed in tuberculous lesions...
April 27, 2018: Biotechnic & Histochemistry: Official Publication of the Biological Stain Commission
Nancy Gupta, Rakesh Kumar, Babita Agrawal
Tuberculosis (TB) is a highly contagious infection and devastating chronic disease, causing 10.4 million new infections and 1.8 million deaths every year globally. Efforts to control and eradicate TB are hampered by the rapid emergence of drug resistance and limited efficacy of the only available vaccine, BCG. Immunological events in the airways and lungs are of major importance in determining whether exposure to Mycobacterium tuberculosis ( Mtb ) results in successful infection or protective immunity. Several studies have demonstrated that the host microbiota is in constant contact with the immune system, and thus continually directs the nature of immune responses occurring during new infections...
2018: Frontiers in Immunology
Sabine Ehrt, Dirk Schnappinger, Kyu Y Rhee
Metabolism was once relegated to the supply of energy and biosynthetic precursors, but it has now become clear that it is a specific mediator of nearly all physiological processes. In the context of microbial pathogenesis, metabolism has expanded outside its canonical role in bacterial replication. Among human pathogens, this expansion has emerged perhaps nowhere more visibly than for Mycobacterium tuberculosis, the causative agent of tuberculosis. Unlike most pathogens, M. tuberculosis has evolved within humans, which are both host and reservoir...
April 24, 2018: Nature Reviews. Microbiology
Shivendra K Chaurasiya
Tuberculosis caused by Mycobacterium tuberculosis remains a global threat for human health. Development of drug resistance and co-infection with human immunodeficiency virus has increased the morbidity and mortality due to tuberculosis. Macrophages serve as primary defense against microbial infections including tuberculosis. Upon recognition and uptake of mycobacteria macrophages initiate a series of events leading to the generation of effective immune response and clearance of infection. On the other hand, pathogen utilizes multiple mechanisms for manipulating macrophage response to protect itself from killing and survive within these cells which are designed for killing them...
April 24, 2018: Microbiology and Immunology
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