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tuberculous pleural effusions: advances and controversies.on a global scale, tuberculosis (tb) remains one of the most frequent causes of pleural effusions. our understanding of the pathogenesis of the disease has evolved and what was once thought to be an effusion as a result of a pure delayed hypersensitivity reaction is now believed to be the consequence of direct infection of the pleural space with a cascade of events including an immunological response. pulmonary involvement is more common than previously believed and induced sputum, which is gros ...201526150911
long noncoding rna derived from cd244 signaling epigenetically controls cd8+ t-cell immune responses in tuberculosis infection.molecular mechanisms for t-cell immune responses modulated by t cell-inhibitory molecules during tuberculosis (tb) infection remain unclear. here, we show that active human tb infection up-regulates cd244 and cd244 signaling-associated molecules in cd8(+) t cells and that blockade of cd244 signaling enhances production of ifn-γ and tnf-α. cd244 expression/signaling in tb correlates with high levels of a long noncoding rna (lncrna)-bc050410 [named as lncrna-as-gstt1(1-72) or lncrna-cd244] in the ...201526150504
structural plasticity in mycobacterium tuberculosis uracil-dna glycosylase (mtung) and its functional implications.17 independent crystal structures of family i uracil-dna glycosylase from mycobacterium tuberculosis (mtung) and its complexes with uracil and its derivatives, distributed among five distinct crystal forms, have been determined. thermodynamic parameters of binding in the complexes have been measured using isothermal titration calorimetry. the two-domain protein exhibits open and closed conformations, suggesting that the closure of the domain on dna binding involves conformational selection. segm ...201526143923
glucose monomycolates based on single synthetic mycolic acids.the preparation of 6-o-mycolylglucoses (gmms) from single synthetic mycolic acids matching the overall structure of some of the major natural glucose monomycolates of mycobacterium tuberculosis and other mycobacteria is reported.201526143625
the external pasta domain of the essential serine/threonine protein kinase pknb regulates mycobacterial growth.pknb is an essential serine/threonine protein kinase required for mycobacterial cell division and cell-wall biosynthesis. here we demonstrate that overexpression of the external pknb_pasta domain in mycobacteria results in delayed regrowth, accumulation of elongated bacteria and increased sensitivity to β-lactam antibiotics. these changes are accompanied by altered production of certain enzymes involved in cell-wall biosynthesis as revealed by proteomics studies. the growth inhibition caused by ...201526136255
drug resistance patterns of mycobacterium tuberculosis complex and associated factors among retreatment cases around jimma, southwest ethiopia.information on the pattern of drug resistant tuberculosis (tb) among re-treatment cases is crucial to develop appropriate control strategies. therefore, we conducted this study to assess the drug resistance pattern of m. tuberculosis complex (mtbc) isolates and associated factors among re-treatment cases in jimma area, southwest ethiopia.201526135909
comparison of three commercial molecular assays for detection of rifampin and isoniazid resistance among mycobacterium tuberculosis isolates in a high-hiv-prevalence setting.in a head-to-head comparison of the mtbdrplus version 2.0 (hain lifescience), the xpert mtb/rif (cepheid), and the anyplex mtb/ntm (seegene) assays, we demonstrated equal sensitivity (59/61; 96.7%) and specificity (53/54; 98.1%) for detecting rifampin resistance with further analysis of discordances. the xpert assay does not detect isoniazid resistance while the anyplex assay showed high false positivity.201526135869
in silico-based high-throughput screen for discovery of novel combinations for tuberculosis treatment.there are currently 18 drug classes for the treatment of tuberculosis, including those in the development pipeline. an in silico simulation enabled combing the innumerably large search space to derive multidrug combinations. through the use of ordinary differential equations (ode), we constructed an in silico kinetic platform in which the major metabolic pathways in mycobacterium tuberculosis and the mechanisms of the antituberculosis drugs were integrated into a virtual proteome. the optimized ...201526149995
likelihood-based inference for discretely observed birth-death-shift processes, with applications to evolution of mobile genetic elements.continuous-time birth-death-shift (bds) processes are frequently used in stochastic modeling, with many applications in ecology and epidemiology. in particular, such processes can model evolutionary dynamics of transposable elements-important genetic markers in molecular epidemiology. estimation of the effects of individual covariates on the birth, death, and shift rates of the process can be accomplished by analyzing patient data, but inferring these rates in a discretely and unevenly observed ...201526148963
xpert mtb/rif test performance assay in respiratory samples at real work settings in a developing country.the xpert mtb/rif test detects dna from mycobacterium tuberculosis complex and susceptibility to rifampin. it has been evaluated repeatedly under "ideal" conditions including centrifugation of sputum and bronchoalveolar lavage, ziehl neelsen (zn) and auramine/rhodamine staining, as well as with solid and liquid automated culture methods. results from such evaluations cannot be extrapolated to low-income countries that do not routinely use all these processes.201526148041
genomics and machine learning for taxonomy consensus: the mycobacterium tuberculosis complex paradigm.infra-species taxonomy is a prerequisite to compare features such as virulence in different pathogen lineages. mycobacterium tuberculosis complex taxonomy has rapidly evolved in the last 20 years through intensive clinical isolation, advances in sequencing and in the description of fast-evolving loci (crispr and miru-vntr). on-line tools to describe new isolates have been set up based on known diversity either on crisprs (also known as spoligotypes) or on miru-vntr profiles. the underlying taxon ...201526154264
simulating the inhibition reaction of mycobacterium tuberculosis l,d-transpeptidase 2 by carbapenems.a theoretical free energy study describes the inactivation of a new tuberculosis target, the l,d-transpeptidase 2 enzyme. a new reaction mechanism of two carbapenem inhibitors is proposed and their molecular features are determined using qm/mm and pmf approaches. the theoretical findings with the new proposed mechanism agree in principle with the experimental data.201526153571
isolated hepatosplenic tuberculosis: a rare presentation.tuberculosis caused by mycobacterium tuberculosis presents a major health challenge in endemic countries and spares no organ in the human body. this infection is a mimicker of various disease processes such as metastasis, lymphoproliferative diseases, and other granulomatous conditions such as sarcoidosis and fungal infections. the most challenging and important differential is metastasis, especially in the disseminated form of tuberculosis. we present a histopathologically proven case of isolat ...201526153294
role of a genotype mtbdrplus line probe assay in early detection of multidrug-resistant tuberculosis at a brazilian reference center.resistance to mycobacterium tuberculosis is a reality worldwide, and its diagnosis continues to be difficult and time consuming. to face this challenge, the world health organization has recommended the use of rapid molecular tests. we evaluated the routine use (once a week) of a line probe assay (genotype mtbdrplus) for early diagnosis of resistance and for assessment of the main related risk factors over 2 years. a total of 170 samples were tested: 15 (8.8%) were resistant, and multidrug resis ...201526132094
analytical and clinical performance of abbott realtime mtb, an assay for detection of mycobacterium tuberculosis in pulmonary specimens.nucleic acid amplification test (naat)-based assays provide fast and sensitive results compared to conventional tb tests. the performance of the new abbott molecular mtb assay for the qualitative detection of mtb complex using the automated m2000™ system or manual sample preparation is summarized in this paper. the assay detects eight mtb complex subspecies. the observed limit of detection (lod) when used to test an mtb h37rv panel was 2.45 colony forming units (cfu)/ml, while the claimed assay ...201526119174
raman spectroscopic monitoring of the growth of pigmented and non-pigmented mycobacteria.raman microspectroscopy has increased in popularity in the field of microbiology because it allows a spectral fingerprinting of bacterial pathogens at an unrivaled speed, which is important for the early treatment of infectious diseases such as tuberculosis. an indispensable prerequisite for the success of this method is a profound knowledge, how the spectral profiles depend on the age of the bacteria. we therefore followed the growth of two rapidly growing mycobacterium tuberculosis relatives, ...201526391403
nr1d1 ameliorates mycobacterium tuberculosis clearance through regulation of autophagy.nr1d1 (nuclear receptor subfamily 1, group d, member 1), an adopted orphan nuclear receptor, is widely known to orchestrate the expression of genes involved in various biological processes such as adipogenesis, skeletal muscle differentiation, and lipid and glucose metabolism. emerging evidence suggests that various members of the nuclear receptor superfamily perform a decisive role in the modulation of autophagy. recently, nr1d1 has been implicated in augmenting the antimycobacterial properties ...201526390081
the xpert® mtb/rif assay in routine diagnosis of pulmonary tuberculosis: a multicentre study in lithuania.drug-resistant tuberculosis (tb) is an important public health problem in lithuania with mdr rates in new cases reaching 11% in 2012. currently available diagnostic tools are not fully adequate for an accurate and rapid result for diagnosis of tb and mdr-tb.201526403251
vitamin d deficiency and tb disease phenotype.extrapulmonary tb is increasingly common, yet the determinants of the wide clinical spectrum of tb are poorly understood.201526400877
countrywide roll-out of xpert(®) mtb/rif in swaziland: the first three years of implementation.all 19 public health laboratories in swaziland that had xpert(®) mtb/rif machines installed as part of a countrywide roll-out between june 2011 and june 2014.201526400386
high-dose vitamin d3 in adults with pulmonary tuberculosis: a double-blind randomized controlled trial.tuberculosis, including multidrug-resistant tuberculosis (mdr-tb), is a major global health problem. individuals with tuberculosis disease commonly exhibit vitamin d deficiency, which may adversely affect immunity and the response to therapy.201526399865
identification and characterization of lipase activity and immunogenicity of lipl from mycobacterium tuberculosis.lipids and lipid-metabolizing esterases/lipases are highly important for the mycobacterial life cycle and, possibly, for mycobacterial virulence. in this study, we expressed 10 members of the lip family of mycobacterium tuberculosis. among the 10 proteins, lipl displayed a significantly high enzymatic activity for the hydrolysis of long-chain lipids. the optimal temperature for the lipase activity of lipl was demonstrated to be 37°c, and the optimal ph was 8.0. the lipase active center was not t ...201526398213
molecular epidemiology of mycobacterium tuberculosis isolates in 100 patients with tuberculosis using pulsed field gel electrophoresis.tuberculosis (tb) is a widespread infectious disease. today, tb has created a public health crisis in the world. genotyping of mycobacterium tuberculosis isolates is useful for surveying the dynamics of tb infection, identifying new outbreaks, and preventing the disease. different molecular methods for clustering of m. tuberculosis isolates have been used.201526396714
core component eccb1 of the mycobacterium tuberculosis type vii secretion system is a periplasmic atpase.pathogenic mycobacteria transport virulence factors across their complex cell wall via a type vii secretion system (t7ss)/early secreted antigenic target-6 of kda secretion system (esx). esx conserved component (ecc) b, a core component of the t7ss architecture, is predicted to be a membrane bound protein, but little is known about its structure and function. here, we characterize eccb1, showing that it is an atpase with no sequence or structural homology to other atpases located in the cell env ...201526396239
structural basis for the regulation of the mmpl transporters of mycobacterium tuberculosis.the mycobacterial cell wall is critical to the virulence of these pathogens. recent work shows that the mmpl (mycobacterial membrane protein large) family of transporters contributes to cell wall biosynthesis by exporting fatty acids and lipidic elements of the cell wall. the expression of the mycobacterium tuberculosis mmpl proteins is controlled by a complex regulatory network, including the tetr family transcriptional regulators rv3249c and rv1816. here we report the crystal structures of the ...201526396194
metabolic modeling predicts metabolite changes in mycobacterium tuberculosis.mycobacterium tuberculosis (mtb) is the causal agent of the disease tuberculosis (tb). metabolic adaptations are thought to be critical to the survival of mtb during pathogenesis. computational tools that can be used to study mtb metabolism in silico and prioritize resource-intensive experimental work could significantly accelerate research.201526377923
the utility of xpert mtb/rif performed on bronchial washings obtained in patients with suspected pulmonary tuberculosis in a high prevalence setting.xpert mtb/rif has been shown to have a superior sensitivity to microscopy for acid fast bacilli (afb) in sputum and has been recommended as a standard first line investigation for pulmonary tuberculosis (ptb). bronchoscopy is a valuable tool in diagnosing ptb in sputum negative patients. there is limited data on the utility of xpert mtb/rif performed on bronchial lavage specimens. our aim was to evaluate the diagnostic efficiency of xpert mtb/rif performed on bronchial washings in sputum scarce/ ...201526377395
determination of in vitro synergy between linezolid and other antimicrobial agents against mycobacterium tuberculosis isolates.in this study, our objective was to explore the potential in vitro synergy between linezolid (lzd) and six other anti-tb drugs in mycobacterium tuberculosis strains, especially multidrug-resistant tuberculosis (mdr-tb) strains. among the different combinations, the lzd-clarithromycin (cla) combination showed the best synergism, which was observed in 85% (34/40) of 40 isolates. in addition, one (2.5%) and twenty-one (52.5%) of 40 isolates showed synergism for the lzd-levofloxcin (lev) and lzd-mox ...201526395151
cough aerosol cultures of mycobacterium tuberculosis: insights on tst / igra discordance and transmission dynamics.the diagnosis of latent tuberculosis (tb) infection (ltbi) is complicated by the absence of a gold standard. discordance between tuberculin skin tests (tst) and interferon gamma release assays (igra) occurs in 10-20% of individuals, but the underlying mechanisms are poorly understood.201526394149
glpx gene in mycobacterium tuberculosis is required for in vitro gluconeogenic growth and in vivo survival.several enzymes involved in central carbon metabolism and gluconeogenesis play a critical role in survival and pathogenesis of mycobacterium tuberculosis (mtb). the only known functional fructose 1,6-bisphosphatase (fbpase) in mtb is encoded by the glpx gene and belongs to the class ii sub-family of fbpase. we describe herein the generation of a δglpx strain using homologous recombination. although the growth profile of δglpx is comparable to that of wild type mtb when grown on the standard enri ...201526397812
association of previous smoking habit and perceived social discrimination with the risk of multi-drug resistant tuberculosis in central nepal.multidrug-resistant tuberculosis (mdr tb) caused by mycobacterium tuberculosis resistant to both isoniazid and rifampicin with or without resistant to other drug, is among the most alarming pandemic problem. the objectives of this study was to assess the risk factors of mdr tb in central nepal.201526411721
validation of a homology model of mycobacterium tuberculosis dxs: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of dxs.the enzyme dxs catalyzes the first, rate-limiting step of the 2-c-methyl-d-erythritol-4-phosphate (mep, 1) pathway using thiamine diphosphate (thdp) as cofactor; the dxs-catalyzed reaction constitutes also the first step in vitamin b1 and b6 metabolism in bacteria. dxs is the least studied among the enzymes of this pathway in terms of crystallographic information, with only one complete crystal structure deposited in the protein data bank (deinococcus radiodurans dxs, pdb: ). we synthesized a se ...201526411373
translating the tuberculosis research agenda: much accomplished, but much more to be done.despite the availability of effective diagnostics and curative treatment regimens for tuberculosis, millions of people die each year of this disease. the steady global increase in the number of tuberculosis cases caused by multidrug-resistant and extensively drug-resistant strains of mycobacterium tuberculosis are of major concern, especially in light of the thin tuberculosis drug pipeline. new tuberculosis drugs are undergoing clinical evaluation, and renewed hope comes from fresh approaches to ...201526409286
b in tb: b cells as mediators of clinically relevant immune responses in tuberculosis.the protective role of b cells and humoral immune responses in tuberculosis infection has been regarded as inferior to cellular immunity directed to the intracellular pathogen mycobacterium tuberculosis. however, b-cell-mediated immune responses in tuberculosis have recently been revisited in the context of b-cell physiology and antigen presentation. we discuss in this review the diverse functions of b cells in tuberculosis, with a focus on their biological and clinical relevance to progression ...201526409285
t-cell therapy: options for infectious diseases.the emergence of drug-resistant tuberculosis is challenging tuberculosis control worldwide. in the absence of an effective vaccine to prevent primary infection with mycobacterium tuberculosis and tuberculosis disease, host-directed therapies may offer therapeutic options, particularly for patients with multidrug-resistant and extensively drug-resistant tuberculosis where prognosis is often limited. cd8(+) and cd4(+) t cells mediate antigen-specific adaptive cellular immune responses. their use i ...201526409284
immune cell regulatory pathways unexplored as host-directed therapeutic targets for mycobacterium tuberculosis: an opportunity to apply precision medicine innovations to infectious diseases.the lack of novel antimicrobial drugs in development for tuberculosis treatment has provided an impetus for the discovery of adjunctive host-directed therapies (hdts). several promising hdt candidates are being evaluated, but major advancement of tuberculosis hdts will require understanding of the master or "core" cell signaling pathways that control intersecting immunologic and metabolic regulatory mechanisms, collectively described as "immunometabolism." core regulatory pathways conserved in a ...201526409283
the distribution of fitness costs of resistance-conferring mutations is a key determinant for the future burden of drug-resistant tuberculosis: a model-based analysis.drug resistance poses a serious challenge for the control of tuberculosis in many settings. it is well established that the expected future trend in resistance depends on the reproductive fitness of drug-resistant mycobacterium tuberculosis. however, the variability in fitness between strains with different resistance-conferring mutations has been largely ignored when making these predictions.201526409276
collaborative effort for a centralized worldwide tuberculosis relational sequencing data platform.continued progress in addressing challenges associated with detection and management of tuberculosis requires new diagnostic tools. these tools must be able to provide rapid and accurate information for detecting resistance to guide selection of the treatment regimen for each patient. to achieve this goal, globally representative genotypic, phenotypic, and clinical data are needed in a standardized and curated data platform. a global partnership of academic institutions, public health agencies, ...201526409275
evolution of extensively drug-resistant tuberculosis over four decades: whole genome sequencing and dating analysis of mycobacterium tuberculosis isolates from kwazulu-natal.the continued advance of antibiotic resistance threatens the treatment and control of many infectious diseases. this is exemplified by the largest global outbreak of extensively drug-resistant (xdr) tuberculosis (tb) identified in tugela ferry, kwazulu-natal, south africa, in 2005 that continues today. it is unclear whether the emergence of xdr-tb in kwazulu-natal was due to recent inadequacies in tb control in conjunction with hiv or other factors. understanding the origins of drug resistance i ...201526418737
recognizing drug targets using evolutionary information: implications for repurposing fda-approved drugs against mycobacterium tuberculosis h37rv.drug repurposing to explore target space has been gaining pace over the past decade with the upsurge in the use of systematic approaches for computational drug discovery. such a cost and time-saving approach gains immense importance for pathogens of special interest, such as mycobacterium tuberculosis h37rv. we report a comprehensive approach to repurpose drugs, based on the exploration of evolutionary relationships inferred from the comparative sequence and structural analyses between targets o ...201526429199
a rare case of concomitant tuberculosis of the nose, paranasal sinuses and larynx: clinical, histological and immunohistochemical aspects. a case report.extrapulmonary tuberculosis is a rare condition determined by mycobacterium tuberculosis. it can affect any organ, and has a higher incidence with the increase of hiv infection, or in countries with high pulmonary tuberculosis. diagnosis is difficult, mostly because of non-specific symptoms and a low rate of presentation for medical consult when symptoms do occur. complete diagnosis is usually set by histological, immunohistochemical examinations, and also with polymerase chain reaction (pcr) in ...201526429181
bone marrow aspirate microscopy v. bone marrow trephine biopsy microscopy for detection of mycobacterium tuberculosis infection.tuberculosis (tb) remains a global health problem. according to the 2013 global report on tuberculosis, 8.6 million people developed tb in 2012 and 1.3 million died from the disease. an estimated 13% of people who developed tb in 2012 were hiv-positive, and 75% of these lived in africa. while pulmonary tb is the commonest form of mycobacterium tuberculosis infection, extrapulmonary tb is increasingly being detected in hiv-positive patients. definitive diagnosis of disseminated tb is a challenge ...201526428979
identification of 13 blood-based gene expression signatures to accurately distinguish tuberculosis from other pulmonary diseases and healthy controls.tuberculosis (tb), caused by infection with mycobacterium tuberculosis, is still a major threat to human health worldwide. current diagnostic methods encounter some limitations, such as sample collection problem or unsatisfied sensitivity and specificity issue. moreover, it is hard to identify tb from some of other lung diseases without invasive biopsy. in this paper, the logistic models with three representative regularization approaches including lasso (the most popular regularization method), ...201526405955
comparison of samples obtained from bronchoscopy of patients with and without bronchial anthracosis for investigating the prevalence of mycobacterium tuberculosis.bronchial anthracosis is caused by the deposition of carbon, silica or asbestos particles in mucosal and submucosal cells and macrophages, and it can lead to chronic bronchial obstruction. certain studies have reported an association between bronchial anthracosis and infection with mycobacterium tuberculosis. this study aimed to compare the samples obtained from bronchoscopy of patients with and without bronchial anthracosis for investigating the prevalence of mycobacterium tuberculosis.201526405675
management of latent mycobacterium tuberculosis infection: who guidelines for low tuberculosis burden countries.latent tuberculosis infection (ltbi) is characterised by the presence of immune responses to previously acquired mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (tb). here we report evidence-based guidelines from the world health organization for a public health approach to the management of ltbi in high risk individuals in countries with high or middle upper income and tb incidence of <100 per 100 000 per year. the guidelines strongly recommend systematic t ...201526405286
report: clinical characteristics and treatment experience report of severe pulmonary infection after renal transplantation.this study was to discuss the clinical diagnosis and treatment features of severe pulmonary infections after renal transplantation, in order to improve the cure rate. retrospective research was applied to analyze the 52 cases of patients with serve pulmonary infection after renal transplantation in the department of organ transplantation in people's hospital of zhengzhou from july, 2008 to december, 2013. the pathogens which caused the pulmonary infection after renal transplantation were bacteri ...201526431655
performance of four transport and storage systems for molecular detection of multidrug-resistant tuberculosis.detection of drug-resistant tuberculosis is essential for the control of the disease but it is often hampered by the limitation of transport and storage of samples from remote locations to the reference laboratory. we performed a retrospective field study to evaluate the performance of four supports enabling the transport and storage of samples to be used for molecular detection of drug resistance using the genotype mtbdrplus.201526431352
human nocardia infections: a review of pulmonary nocardiosis.human nocardiosis may present as an acute or a chronic infection. although a saprophyte nocardia spp are responsible for superficial skin infections, pulmonary infections, and disseminated nocardiosis usually involving patients who are immunosuppressed and debilitated. infections in immunocompetent individuals are usually chronic and present non-specific symptoms. invasive and disseminated nocardiosis is common among patients with weakened cellular immune systems. clinical diagnosis of pulmonary ...201526430578
e1 of α-ketoglutarate dehydrogenase defends mycobacterium tuberculosis against glutamate anaplerosis and nitroxidative stress.enzymes of central carbon metabolism (ccm) in mycobacterium tuberculosis (mtb) make an important contribution to the pathogen's virulence. evidence is emerging that some of these enzymes are not simply playing the metabolic roles for which they are annotated, but can protect the pathogen via additional functions. here, we found that deficiency of 2-hydroxy-3-oxoadipate synthase (hoas), the e1 component of the α-ketoglutarate (α-kg) dehydrogenase complex (kdhc), did not lead to general metabolic ...201526430237
genome comparison of an ancestral isolate and a modern isolate of mycobacterium tuberculosis of the beijing lineage from são paulo, brazil.mycobacterium tuberculosis of the bejing subtype (mtbb) is transmitted efficiently in high burden countries for this genotype. a higher virulence was associated with isolates of the "modern" beijing genotype sub-lineages when compared to "ancient" ones. here, we report the full genomes of the strain representing these two genotypes from brazil, a country with a low incidence of mtbb.201526430044
characterization of cd4/cd8+ αβ and vγ2vδ2+ t cells in hiv-negative individuals with different mycobacterium tuberculosis infection statuses.the immune responses of t cell subsets among patients with different mycobacterium tuberculosis (m.tb) infection statuses [i.e., active tuberculosis (atb), latent tuberculosis infection (ltbi) and non-infection (healthy control, hc)] have not been fully elucidated in hiv-negative individuals. specifically, data are limiting in high tuberculosis epidemic regions in china. to investigate the distributions and functions of t cell subsets (i.e., cd3+, cd4+, cd8+ αβ and vγ2vδ2+ t cells) in hiv-negati ...201526429305
lack of intracellular replication of m. tuberculosis and m. bovis bcg caused by delivering bacilli to lysosomes in murine brain microvascular endothelial cells.invasion and traversal of the blood-brain barrier (bbb) by mycobacterium tuberculosis cause meningeal tuberculosis (tb) in the central nervous system (cns). meningeal tb is a serious, often fatal disease that disproportionately affects young children. the mechanisms involved in cns invasion by m. tuberculosis bacilli are poorly understood. in this study, we microscopically examined endosomal trafficking and measured survival of m. tuberculosis and m. bovis bacille calmette-guérin (bcg) bacilli i ...201526440149
dynamics of immune parameters during the treatment of active tuberculosis showing negative interferon gamma response at the time of diagnosis.in the performance of interferon gamma release assays (igra) for the diagnosis of tuberculosis (tb) infection, false-negative results are a major obstacle. in active tb patients, treatment-dependent changes of the negative test results remain unknown.201526439971
ppe26 induces tlr2-dependent activation of macrophages and drives th1-type t-cell immunity by triggering the cross-talk of multiple pathways involved in the host response.the pathophysiological functions and the underlying molecular basis of pe /ppe proteins of m. tuberculosis remain largely unknown. in this study, we focused on the link between ppe26 and host response. we demonstrated that ppe26 can induce extensive inflammatory responses in macrophages through triggering the cross-talk of multiple pathways involved in the host response, as revealed by itraq-based subcellular quantitative proteomics. we observed that ppe26 is able to specifically bind to tlr2 le ...201526439698
one of these is not like the others.a mycobacterium tuberculosis meta mutant that is auxotrophic for methionine is unlike other auxotrophic mutants of this important species as methionine starvation results in rapid death instead of cessation of growth. evidence suggests that this phenotype results from starvation affecting essential pathways that utilize s-adenosylmethionine in addition to methionine.201526439291
peptidoglycan synthesis in mycobacterium tuberculosis is organized into networks with varying drug susceptibility.peptidoglycan (pg), a complex polymer composed of saccharide chains cross-linked by short peptides, is a critical component of the bacterial cell wall. pg synthesis has been extensively studied in model organisms but remains poorly understood in mycobacteria, a genus that includes the important human pathogen mycobacterium tuberculosis (mtb). the principle pg synthetic enzymes have similar and, at times, overlapping functions. to determine how these are functionally organized, we carried out who ...201526438867
esters of pyrazinoic acid are active against pyrazinamide-resistant strains of mycobacterium tuberculosis and other naturally resistant mycobacteria in vitro and ex vivo within macrophages.pyrazinamide (pza) is active against major mycobacterium tuberculosis species (m. tuberculosis, m. africanum, and m. microti) but not against m. bovis and m. avium. the latter two are mycobacterial species involved in human and cattle tuberculosis and in hiv coinfections, respectively. pza is a first-line agent for the treatment of human tuberculosis and requires activation by a mycobacterial pyrazinamidase to form the active metabolite pyrazinoic acid (poa). as a result of this mechanism, resis ...201526438493
peritoneal tuberculosis presenting with portal vein thrombosis and transudative ascites - a diagnostic dilemma: case report.peritoneal tuberculosis is an important problem in regions of the world where tuberculosis is still prevalent (chest 1991; 99:1134). atypical presentations such as portal vein thrombosis can delay diagnosis or result in misdiagnosis (gut 1990; 31:1130, acta clinbelg 2012; 67(2):137-9, j cytol histol 2014; 5:278, digestive diseases and sciences 1991; 36(1):112-115). a high index of suspicion is required for the diagnosis of peritoneal tuberculosis, as the analysis of peritoneal fluid for tubercul ...201526423615
a single-nucleotide-polymorphism real-time pcr assay for genotyping of mycobacterium tuberculosis complex in peri-urban kampala.accurate and high-throughput genotyping of mycobacterium tuberculosis complex (mtbc) may be important for understanding the epidemiology and pathogenesis of tuberculosis (tb). in this study, we report the development of a lightcycler® real-time pcr single-nucleotide-polymorphism (lrps) assay for the rapid determination of mtbc lineages/sublineages in minimally processed sputum samples from tb patients.201526423522
differential expression of putative drug resistance genes in mycobacterium tuberculosis clinical isolates.understanding drug resistance in mycobacterium tuberculosis requires an integrated analysis of strain lineages, mutations and gene expression. previously, we reported the differential expression of esxg, esxh, infa, groes, rpmi, rpsa and lipf genes in a sensitive m. tuberculosis strain and in a multidrug-resistant clinical isolate. here, we have evaluated the expression of these genes in 24 clinical isolates that belong to different lineages and have different drug resistance profiles. in vitro, ...201526454220
engagement of the aryl hydrocarbon receptor in mycobacterium tuberculosis-infected macrophages has pleiotropic effects on innate immune signaling.understanding the mechanisms of host macrophage responses to mycobacterium tuberculosis is essential for uncovering potential avenues of intervention to boost host resistance to infection. macrophage transcriptome profiling revealed that m. tuberculosis infection strongly induced the expression of several enzymes controlling tryptophan catabolism. these included ido1 and tryptophan 2,3-dioxygenase, which catalyze the rate-limiting step in the kynurenine pathway, producing ligands for the aryl hy ...201526416282
diagnosis of pulmonary and extrapulmonary tuberculosis based on detection of mycobacterial antigen 85b by immuno-pcr.we developed a novel indirect sandwich immuno-polymerase chain reaction (i-pcr) assay for the detection of mycobacterial antigen 85b (ag85b, 30kda, rv1886c) in pulmonary tuberculosis (ptb) and extrapulmonary tuberculosis (eptb) patients. the amino-modified reporter dna was covalently attached with the antidetection antibody through a heterobifunctional cross-linking agent succinimidyl 4-[n-maleimidomethyl]-cyclohexane-1-carboxylate. the detection limit of ag85b by i-pcr was found to be 1 femtogr ...201526422085
in vitro activity against mycobacterium tuberculosis of levofloxacin, moxifloxacin and ub-8902 in combination with clofazimine and pretomanid.multidrug resistance has become a problem in the management of tuberculosis, with an urgent need for research into new drugs as well as the development of efficacious drug combinations and regimens. the main objective of this study was to assess and compare the efficacy of three antituberculous combinations (clofazimine/pretomanid/levofloxacin, clofazimine/pretomanid/moxifloxacin and clofazimine/pretomanid/ub-8902) against multidrug-resistant (mdr) and drug-susceptible clinical isolates of mycob ...201526421981
[urinary tuberculosis: serious complications may occur when diagnosis is delayed].genitourinary tuberculosis is the third most common form of extrapulmonary tuberculosis, comprising 4 - 17% of extrapulmonary forms. the authors describe the case of a patient with recurrent urinary tract infections, without isolation of an infectious agent and without symptomatic resolution, despite antibiotic treatment. imaging exams showed left ureteral stenosis with moderate hydronephrosis. the attempt of retrograde catheterization was impossible so we opted for percutaneous nephrostomy to r ...201526421792
profile of interferon-gamma response to latency-associated and novel in vivo expressed antigens in a cohort of subjects recently exposed to mycobacterium tuberculosis.recently some latency-associated antigens (laa) of mycobacterium tuberculosis were described, as rv2029c, rv2031c, rv2034, rv2628 and rv3353c. of which, the rv2034 and rv3353c also demonstrated in vivo expression. therefore evaluating the immune response to these antigens may help to understand their role in latent tb infection. in a 1-year longitudinal study, ifn-γ response by in vitro peripheral blood mononuclear cells stimulation with laa was investigated in subjects recently exposed to tb, c ...201526421415
analysis of the molecular evolution of the mycobacterium tuberculosis drug-resistant gene rpob in asia using a bayesian evolutionary method.tuberculosis (tb) is a serious communicable disease throughout the world. re-emergence of the tb epidemic is aggravated by the circulation of multidrug-resistant mycobacterium tuberculosis strains, and more than half of new cases have occurred in asia. therefore, it is important to understand the gene mutations underlying the development of rifampicin resistance in asia.201526427147
update in mycobacterium tuberculosis lung disease 2014. 201526426784
multi-etiological nature of tuberculosis-like lesions in condemned pigs at the slaughterhouse.tuberculosis-like lesions (tbl) in pigs have been associated with microorganisms other than mycobacteria. in this work a histopathological and microbiological evaluation of tbl in pigs is shown. a total of 352 samples belonging to 171 pigs totally condemned at slaughterhouse due to generalized tbl were sampled and selected for analysis. pyogranulomatous (56.2%) and granulomatous lesions (20.2%) were observed in all analysed organs. most of the granulomas observed in both lymph nodes and lungs be ...201526418681
phosphorylation of mycobacterium tuberculosis protein tyrosine kinase a ptka by ser/thr protein kinases.mycobacterium tuberculosis (mtb), the causative agent of tuberculosis (tb), has inflicted about one third of mankind and claims millions of deaths worldwide annually. signalling plays an important role in mtb pathogenesis and persistence, and thus represents attractive resource for drug target candidates. here, we show that protein tyrosine kinase a (ptka) can be phosphorylated by mtb endogenous eukaryotic-like ser/thr protein kinases (estpks). kinase assays showed that pkna, pknd, pknf, and pkn ...201526417687
mutations found in embcab, embr, and ubia genes of ethambutol-sensitive and -resistant mycobacterium tuberculosis clinical isolates from china.to better understand the molecular mechanisms of ethambutol (emb) resistance, the mutant hot spot region of five genes (embb, emba, embc, embr, and ubia) was amplified and sequenced in 109 emb-resistant and 153 emb-susceptible clinical isolates from china. twenty-seven emb-susceptible isolates were found to have nonsynonym mutations, 23 of which were in embb. the mutations occurred most frequently in embb (85.3%, 93) and were seldom in embc (2.8%, 3), emba (3.7%, 4), embr (3.7%, 4), and ubia (8. ...201526417605
novel epitopes identified from efflux pumps of mycobacterium tuberculosis could induce cytotoxic t lymphocyte response.overcoming drug-resistance is one of the major challenges to control tuberculosis (tb). the up-regulation of efflux pumps is one common mechanism that leads to drug-resistance. therefore, immunotherapy targeting these efflux pump antigens could be promising strategy to be combined with current chemotherapy. considering that cd8+ cytotoxic t lymphocytes (ctls) induced by antigenic peptides (epitopes) could elicit hla-restricted anti-tb immune response, efflux pumps from classical abc family (myco ...201526417538
evolution of mycolic acid biosynthesis genes and their regulation during starvation in mycobacterium tuberculosis.mycobacterium tuberculosis, the etiological agent of tuberculosis, is a gram-positive bacterium with a unique cell envelope composed of an essential outer membrane. mycolic acids, which are very-long-chain (up to c100) fatty acids, are the major components of this mycomembrane. the enzymatic pathways involved in the biosynthesis and transport of mycolates are fairly well documented and are the targets of the major antituberculous drugs. in contrast, only fragmented information is available on th ...201526416833
antigen-specific human nkt cells from tuberculosis patients produce il-21 to help b cells for the production of immunoglobulins.natural killer t (nkt) cells from mouse and human play an important role in the immune responses against mycobacterium tuberculosis. however, the function of cd3(+)tcrvβ11(+) nkt cells at the local site of m. tuberculosis infection remains poorly defined. in the present study, we found that after stimulation with m. tuberculosis antigens, nkt cells isolated from tuberculosis (tb) pleural fluid mononuclear cells (pfmcs) produced il-21 and other cytokines including ifn-γ, tnf-α, il-2 and il-17. il ...201526416419
a mycobacterium tuberculosis dormancy antigen differentiates latently infected bacillus calmette-guérin-vaccinated individuals.ifn-γ release assays (igras) are better indicators of mycobacterium tuberculosis infection than the tuberculin skin test (tst) in bacillus calmette-guérin (bcg)-vaccinated populations. however, igras do not discriminate active and latent infections (ltbi) and no gold standard for ltbi diagnosis is available. thus, since improved tests to diagnose m. tuberculosis infection are required, we assessed the efficacy of several m. tuberculosis latency antigens. bcg-vaccinated healthy donors (hd) and tu ...201526425695
distribution and transmission of mycobacterium tuberculosis complex lineages among children in peri-urban kampala, uganda.to gain insight into the transmission of tuberculosis (tb) in peri-urban kampala-uganda, we performed a household contact study using children as a surrogate for recent transmission of mycobacterium tuberculosis (mtb). using this approach, we sought to understand m. tuberculosis complex (mtbc) lineage diversity, distribution and how these relate to tb transmission to exposed children.201526424324
efficient calculation of enzyme reaction free energy profiles using a hybrid differential relaxation algorithm: application to mycobacterial zinc hydrolases.determination of the free energy profile for an enzyme reaction mechanism is of primordial relevance, paving the way for our understanding of the enzyme's catalytic power at the molecular level. although hybrid, mostly dft-based, qm/mm methods have been extensively applied to this type of studies, achieving accurate and statistically converged results at a moderate computational cost is still an open challenge. recently, we have shown that accurate results can be achieved in less computational t ...201526415840
phenothiazines as a solution for multidrug resistant tuberculosis: from the origin to present.historically, multiplicity of actions in synthetic compounds is a rule rather than exception. the science of non-antibiotics evolved in this background. from the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed. the phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. the emergence of h ...201526415662
rapid, single-cell electrochemical detection of mycobacterium tuberculosis using colloidal gold nanoparticles.tuberculosis (tb) remains a global health threat, with over a third of the world population suffering from the disease, and 1.5 million deaths due to the disease in 2013 alone. despite significant advances in tb detection strategies in recent years, a bigger push toward detecting tb in the shortest and easiest way possible at the point-of-care (poc) is still in demand. to this end, we have designed a simple yet rapid and sensitive bioassay that detects mtb dna electrochemically using colloidal g ...201526382883
mycobacterium tuberculosis is resistant to isoniazid at a slow growth rate by single nucleotide polymorphisms in katg codon ser315.an important aim for improving tb treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. in any m. tuberculosis population there is a proportion of bacteria that are drug-tolerant; this might be because of pre-existing populations of slow growing/non replicating bacteria that are protected from antibiotic action due to the expression of a phenotype that limits drug activity. we addressed this quest ...201526382066
morphological changes in the overall mycobacterium tuberculosis h37ra cell shape and cytoplasm homogeneity due to mutellina purpurea l. essential oil and its main constituents.the aim of this study was to evaluate the antimycobacterial activity of the essential oil (eo) of mutellina purpurea l. and its main constituents against the m. tuberculosis h37ra strain.201526381133
mtb-dr-rif 9g test: detection and discrimination of tuberculosis and multi-drug resistant tuberculosis strains.this report describes the evaluation of the novel mtb-dr-rif 9g test for the accurate detection and discrimination of mycobacterium tuberculosis (mtb) and rifampicin-resistant m. tuberculosis (mtb-dr-rif) in the clinical samples. the procedure included the amplification of a nucleotide fragment of the rpob gene of the mtb and mtb-dr-rif strains and their hybridization with the immobilized probes. the mtb-dr-rif 9g test was evaluated for its ability to detect and discriminate mtb and mtb-dr-rif s ...201526381057
perianal tuberculosis: a case report and review of the literature.tuberculosis (tb) is still a major health problem worldwide. we present a rare case of an immuno-competent patient with perianal tb. a 38-year-old man visited a clinic with pain, swelling, and redness in the perineum. he had been persistently coughing for the past 6 mo. the abscess had formed a fistula to the perianal region, indicating perianal abscess. mycobacterium tuberculosis was found in sputum and perianal abscess. surgical drainage was performed, and oral anti-tuberculous drugs were admi ...201526380834
expression and purification of the recombinant cytochrome p450 cyp141 protein of mycobacterium tuberculosis as a diagnostic tool and vaccine production.tuberculosis (tb) is regarded as a health problem worldwide, particularly in developing countries. mycobacterium tuberculosis (m. tuberculosis) is the cause of this disease. approximately two billion people worldwide are infected by m. tuberculosis and annually about two million individuals die in consequence. forty million people are estimated to die because of m. tuberculosis over the next 25 years if the measures for controlling this infection are not extensively developed. in the vaccination ...201526380105
pyrosequencing analysis for mutations in embb codon306 among clinical mycobacterium tuberculosis isolates from qingdao, china.in this study, our objectives was to analyze the molecular characteristics of mutation at embb codon306 in mycobacterium tuberculosis in qingdao by pyrosequencing technology, and to assess the value of embb codon306 used as a molecular marker to diagnose multidrug resistant (mdr) tb strains. pyrosequencing was used to detect mutations at embb codon306 among m. tuberculosis isolates from tuberculosis (tb) patients in qingdao. the correlation between embb306 mutation and mdr phenotype was evaluate ...201526379935
b cells and programmed death-ligand 2 signaling are required for maximal interferon-γ recall response by splenic cd4⁺ memory t cells of mice vaccinated with mycobacterium tuberculosis ag85b.cd4+ t cells producing interferon-γ are crucial for protection against mycobacterium tuberculosis infection and are the cornerstone of tuberculosis vaccination and immunological diagnostic assays. since emerging evidence indicates that b cells can modulate t cell responses to m. tuberculosis infection, we investigated the contribution of b cells in regulating interferon-γ recall response by memory thelper1 cells specific for ag85b, a leading candidate for tuberculosis sub-unit vaccines. we found ...201526379242
the etiology of lower respiratory tract infections in people with diabetes.patients with diabetes mellitus (dm) are likely to develop many types of infections, which affect the transport of glucose into tissues. diabetes increases the susceptibility to different kinds of respiratory infections, is often identified as an independent risk factor for developing lower respiratory tract infections. pulmonary infections caused by mycobacterium tuberculosis, staphylococcus aureus, gram-negative bacteria and fungi may occur with an increased frequency, whereas infections due t ...201526379004
middle lobe syndrome: an extraordinary presentation of endobronchial tuberculosis.tuberculous infection of the tracheobronchial tree, termed as endobronchial tuberculosis (ebtb), is more common in young adults and females. this clinical entity is poorly understood and the diagnosis is frequently delayed as sputum smears are often negative for acid fast bacilli and the chest radiograph can be normal, resulting in diagnostic confusion. bronchoscopy continues to play a key role in its diagnosis. though atelectasis is not uncommon in these patients, ebtb presenting as a middle lo ...201526379001
synthesis, antibacterial and antitubercular activities of some 5h-thiazolo[3,2-a]pyrimidin-5-ones and sulfonic acid derivatives.a series of 5h-thiazolo[3,2-a]pyrimidin-5-ones were synthesized by the cyclization reactions of s-alkylated derivatives in concentrated h₂so₄. upon treatment of s-alkylated derivatives at different temperatures, intramolecular cyclization to 7-(substituted phenylamino)-5h-thiazolo[3,2-a]pyrimidin-5-ones or sulfonation of cyclized products to sulfonic acid derivatives occurred. the structures of the target compounds were confirmed by ir, ¹h-nmr, (13)c-nmr and hrms studies. the compounds were eval ...201526378507
improved detection by next-generation sequencing of pyrazinamide resistance in mycobacterium tuberculosis isolates.the technical limitations of common tests used for detecting pyrazinamide (pza) resistance in mycobacterium tuberculosis isolates pose challenges for comprehensive and accurate descriptions of drug resistance in patients with multidrug-resistant tuberculosis (mdr-tb). in this study, a 606-bp fragment (comprising the pnca coding region plus the promoter) was sequenced using ion torrent next-generation sequencing (ngs) to detect associated pza resistance mutations in 88 recultured mdr-tb isolates ...201526378284
lupus vulgaris mimicking hemangioma diagnosed 42 years after onset: a case report.lupus vulgaris is the most common form of cutaneous tuberculosis. it may easily be overlooked if a proper differential diagnosis is omitted.201526376746
tuberculous lymphadenitis in ethiopia predominantly caused by strains belonging to the delhi/cas lineage and newly identified ethiopian clades of the mycobacterium tuberculosis complex.recently, newly defined clades of mycobacterium tuberculosis complex (mtbc) strains, namely ethiopia 1-3 and ethiopia h37rv-like strains, and other clades associated with pulmonary tb (ptb) were identified in ethiopia. in this study, we investigated whether these new strain types exhibit an increased ability to cause tb lymphadenitis (tbln) and raised the question, if particular mtbc strains derived from tbln patients in northern ethiopia are genetically adapted to their local hosts and/or to th ...201526376441
clinical predictors of culture-confirmed pulmonary tuberculosis in children in a high tuberculosis and hiv prevalence area.the burden of childhood tuberculosis (tb) remains significant especially in areas of high hiv prevalence. clinical diagnosis predominates, despite advances in molecular and microbiological diagnostics. the aim of this study is to identify clinical features associated with culture-confirmed pulmonary tb (ptb) in children.201526376315
latent mycobacterium tuberculosis infection. 201526376153
latent mycobacterium tuberculosis infection. 201526376152
latent mycobacterium tuberculosis infection. 201526376151
latent mycobacterium tuberculosis infection. 201526376150
latent mycobacterium tuberculosis infection. 201526376149
synthetic and immunological studies of mycobacterial lipoarabinomannan oligosaccharides and their protein conjugates.lipoarabinomannan (lam) is one of the major constituents of the mycobacterium tuberculosis cell wall and an attractive molecular scaffold for antituberculosis drug and vaccine development. in this paper, a convergent strategy was developed for the synthesis of lam oligosaccharides with an α-1,2-linked dimannopyranose cap at the nonreducing end. the strategy was highlighted by efficient coupling of separately prepared nonreducing end and reducing end oligosaccharides. glycosylations were mainly a ...201526375482
epigenetics and proteomics join transcriptomics in the quest for tuberculosis biomarkers.an estimated one-third of the world's population is currently latently infected with mycobacterium tuberculosis. latent m. tuberculosis infection (ltbi) progresses into active tuberculosis (tb) disease in ~5 to 10% of infected individuals. diagnostic and prognostic biomarkers to monitor disease progression are urgently needed to ensure better care for tb patients and to decrease the spread of tb. biomarker development is primarily based on transcriptomics. our understanding of biology combined w ...201526374119
rp105 engages phosphatidylinositol 3-kinase p110δ to facilitate the trafficking and secretion of cytokines in macrophages during mycobacterial infection.cytokines are key regulators of adequate immune responses to infection with mycobacterium tuberculosis. we demonstrate that the p110δ catalytic subunit of pi3k acts as a downstream effector of the tlr family member rp105 (cd180) in promoting mycobacteria-induced cytokine production by macrophages. our data show that the significantly reduced release of tnf and il-6 by rp105(-/-) macrophages during mycobacterial infection was not accompanied by diminished mrna or protein expression. mycobacteria ...201526371254
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