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suppression of mcl-1 induces apoptosis in mouse peritoneal macrophages infected with mycobacterium tuberculosis.the effect of myeloid cell leukemia-1 (mcl-1) inhibition on apoptosis of peritoneal macrophages in mice infected with mycobacterium tuberculosis was investigated and the primary signaling pathway associated with the transcriptional regulation of mcl-1 was identified. real-time pcr and western blotting indicated that mcl-1 transcript and protein expression are upregulated during infection with virulent m. tuberculosis h37rv and xinjiang strains but not with attenuated m. tuberculosis strain h37ra ...201626876933
crystal structure of mycobacterium tuberculosis ketol-acid reductoisomerase at 1.0 å resolution - a potential target for anti-tuberculosis drug discovery.the biosynthetic pathway for the branched-chain amino acids is present in plants, fungi and bacteria, but not in animals, making it an attractive target for herbicidal and antimicrobial drug discovery. ketol-acid reductoisomerase (kari; ec 1.1.1.86) is the second enzyme in this pathway, converting in a mg(2+) - and nadph-dependent reaction either 2-acetolactate or 2-aceto-2-hydroxybutyrate to their corresponding 2,3-dihydroxy-3-alkylbutyrate products. here, we have determined the crystal structu ...201626876563
epidemiological, clinical and laboratory profiles of cutaneous polyarteritis nodosa patients: report of 22 cases and literature review.cutaneous polyarteritis nodosa (cpan) is a rare disease that affects small and middle caliber vessels of the deep dermis and subcutaneous tissue and its etiopathology remains yet to be understood.201626876385
downregulation of vimentin in macrophages infected with live mycobacterium tuberculosis is mediated by reactive oxygen species.mycobacterium tuberculosis persists primarily in macrophages after infection and manipulates the host defence pathways in its favour. 2d gel electrophoresis results showed that vimentin, an intermediate filament protein, is downregulated in macrophages infected with live mycobacterium tuberculosis h37rv when compared to macrophages infected with heat- killed h37rv. the downregulation was confirmed by western blot and quantitative rt-pcr. besides, the expression of vimentin in avirulent strain, m ...201626876331
cytokine production and mrna expression in pulmonary tuberculosis patients and their household contacts of younger age group (15-25years).household contacts of tuberculosis patients are at high risk of infection and development of active disease. in this study we evaluated the cytokine production and mrna expression of ifn-γ, tnf-α, il-10&il-6 stimulated with r32kda m. bovis bcgag in active pulmonary tuberculosis patients (aptb), household contacts (hhc) and healthy controls (hc). the results showed the stimulated levels of ifn-γ and tnf-α were low while il-10 levels were high in aptb and hhc compared to hc. il-6 has not shown any ...201626876300
protonation state of f420h2 in the prodrug-activating deazaflavin dependent nitroreductase (ddn) from mycobacterium tuberculosis.the protonation state of the deazaflavin dependent nitroreductase (ddn) enzyme bound cofactor f420 was investigated using uv-visible spectroscopy and computational simulations. the reduced cofactor f420h2 was determined to be present in its deprotonated state in the holoenzyme form. the mechanistic implications of these findings are discussed.201626876228
synthesis and pharmacological evaluation of nucleoside prodrugs designed to target siderophore biosynthesis in mycobacterium tuberculosis.the nucleoside antibiotic, 5'-o-[n-(salicyl)sulfamoyl]adenosine (1), possesses potent whole-cell activity against mycobacterium tuberculosis (mtb), the etiological agent of tuberculosis (tb). this compound is also active in vivo, but suffers from poor drug disposition properties that result in poor bioavailability and rapid clearance. the synthesis and evaluation of a systematic series of lipophilic ester prodrugs containing linear and α-branched alkanoyl groups from two to twelve carbons at the ...201626875934
antimycobacterial and cytotoxic activity of selected medicinal plant extracts.tuberculosis (tb) caused by mycobacterium tuberculosis remains an ongoing threat to human health. several medicinal plants are used traditionally to treat tuberculosis in ghana. the current study was designed to investigate the antimycobacterial activity and cytotoxicity of crude extracts from five selected medicinal plants.201626875647
detection of multidrug-resistant mycobacterium tuberculosis strains isolated in brazil using a multimarker genetic assay for katg and rpob genes.multidrug-resistant tuberculosis (mdrtb) is a serious world health problem that limits public actions to control tuberculosis, because the most used anti-tuberculosis first-line drugs fail to stop mycobacterium spread. consequently, a quick detection through molecular diagnosis is essential to reduce morbidity and medical costs. despite the availability of several molecular-based commercial-kits to diagnose multidrug-resistant tuberculosis, their diagnostic value might diverge worldwide since my ...201626874220
cutting edge: mycobacterium tuberculosis induces aerobic glycolysis in human alveolar macrophages that is required for control of intracellular bacillary replication.recent advances in immunometabolism link metabolic changes in stimulated macrophages to production of il-1β, a crucial cytokine in the innate immune response to mycobacterium tuberculosis. to investigate this pathway in the host response to m. tuberculosis, we performed metabolic and functional studies on human alveolar macrophages, human monocyte-derived macrophages, and murine bone marrow-derived macrophages following infection with the bacillus in vitro. m. tuberculosis infection induced a sh ...201626873991
il-17ra in non-hematopoietic cells controls cxcl-1 and 5 critical to recruit neutrophils to the lung of mycobacteria-infected mice during the adaptive immune response.during chronic infection with mycobacterium tuberculosis (mtb), bacilli multiplication is constrained within lung granulomas until excessive inflammation destroys the lung. neutrophils are recruited early and participate in granuloma formation, but excessive neutrophilia exacerbates the tuberculosis disease. neutrophils thus appear as potential targets for therapeutic interventions, especially in patients for whom no antibiotic treatment is possible. signals that regulate neutrophil recruitment ...201626871571
drug-resistant tb: deadly, costly and in need of a vaccine.tb is an underappreciated public health threat in developed nations. in 2014, an estimated 9.6 million tb cases and 1.5 million deaths occurred worldwide; 3.3% of these cases resulted from multidrug-resistant tuberculosis (mdr-tb) and extensively drug-resistant tuberculosis (xdr-tb) strains. these figures underestimate the economic burden associated with mdr-tb and xdr-tb, as the cost of treating disease caused by these strains can be 9-25 times higher than treating drug-susceptible tb. developi ...201626884499
comparative study of activities of a diverse set of antimycobacterial agents against mycobacterium tuberculosis and mycobacterium ulcerans.a library of compounds covering a broad chemical space was selected from a tuberculosis drug development program and was screened in a whole-cell assay against mycobacterium ulcerans, the causative agent of the necrotizing skin disease buruli ulcer. while a number of potent antitubercular agents were only weakly active or inactive against m. ulcerans, five compounds showed high activity (90% inhibitory concentration [ic90], ≤1 μm), making screening of focused antitubercular libraries a good star ...201626883701
phenotypically adapted mycobacterium tuberculosis populations from sputum are tolerant to first-line drugs.tuberculous sputum contains multiplemycobacterium tuberculosispopulations with different requirements for isolationin vitro these include cells that form colonies on solid media (plateablem. tuberculosis), cells requiring standard liquid medium for growth (nonplateablem. tuberculosis), and cells requiring supplementation of liquid medium with culture supernatant (sn) for growth (sn-dependentm. tuberculosis). here, we describe protocols for the cryopreservation and direct assessment of antimicrob ...201626883695
effects of b cell depletion on early mycobacterium tuberculosis infection in cynomolgus macaques.although recent studies in mice have shown that components of b cell and humoral immunity can modulate the immune responses against mycobacterium tuberculosis, the roles of these components in human and nonhuman primate infections are unknown. the cynomolgus macaque (macaca fascicularis) model of m. tuberculosis infection closely mirrors the infection outcomes and pathology in human tuberculosis (tb). the present study used rituximab, an anti-cd20 antibody, to deplete b cells in m. tuberculosis- ...201626883591
lipoarabinomannan-responsive polycytotoxic t cells are associated with protection in human tuberculosis.the development of host-targeted, prophylactic, and therapeutic interventions against tuberculosis requires a better understanding of the immune mechanisms that determine the outcome of infection with mycobacterium tuberculosis.201626882070
stable alkynyl glycosyl carbonates: catalytic anomeric activation and synthesis of a tridecasaccharide reminiscent of mycobacterium tuberculosis cell wall lipoarabinomannan.oligosaccharide synthesis is still a challenging task despite the advent of modern glycosidation techniques. herein, alkynyl glycosyl carbonates are shown to be stable glycosyl donors that can be activated catalytically by gold and silver salts at 25 °c in just 15 min to produce glycosides in excellent yields. benzoyl glycosyl carbonate donors are solid compounds with a long shelf life. this operationally simple protocol was found to be highly efficient for the synthesis of nucleosides, amino ac ...201626879797
[clinicoradiologic characteristics of active pulmonary tuberculosis with perilymphatic involvement].to evaluate the prevalence of perilymphatic involvement and clinicoradiologic characteristics of active pulmonary tuberculosis according to the distribution of micronodules on ct images.201626879715
high il-6 and low il-15 levels mark the presence of tb infection: a preliminary study.the host immune response, apart from mycobacterial factors, is a significant determinant in the development of tuberculosis (tb). the purpose of the study was to examine whether the differential serum profiles of cytokines il-1β, il-2, il-4, il-6, il-10, il-15, ifn-γ, tgf-β, and tnf-α could discriminate between tb patients and healthy controls and provide insights into pathogenesis. serum samples from tb patients, tb patient contacts and healthy controls were collected and analyzed by elisa. the ...201626878649
treatment of mycobacterium tuberculosis-infected macrophages with poly(lactic-co-glycolic acid) microparticles drives nfκb and autophagy dependent bacillary killing.the emergence of multiple-drug-resistant tuberculosis (mdr-tb) has pushed our available repertoire of anti-tb therapies to the limit of effectiveness. this has increased the urgency to develop novel treatment modalities, and inhalable microparticle (mp) formulations are a promising option to target the site of infection. we have engineered poly(lactic-co-glycolic acid) (plga) mps which can carry a payload of anti-tb agents, and are successfully taken up by human alveolar macrophages. even withou ...201626894562
structure of the ectodomain of the electron transporter rv2874 from mycobacterium tuberculosis reveals a thioredoxin-like domain combined with a carbohydrate-binding module.the members of the ccda family are integral membrane proteins that use a disulfide cascade to transport electrons from the thioredoxin-thioredoxin reductase system in the interior of the cell into the extracytoplasmic space. the core transmembrane portion of this family is often elaborated with additional hydrophilic domains that act as adapters to deliver reducing potential to targets outside the cellular membrane. to investigate the function of family members in mycobacterium tuberculosis, the ...201626894533
crescentic glomerulonephritis associated with pulmonary tuberculosis.tuberculosis of kidney and urinary tract is caused by members of the mycobacterium tuberculosis complex. kidney is usually infected by haematogenous spread of bacilli from focus of infection in the lungs. glomerular involvement in tuberculosis presenting as a rapidly progressive glomerulonephritis is a rare entity. we report a rare case of crescentic glomerulonephritis associated with pulmonary tuberculosis in a 26-year-old man. patient was treated with corticosteroids, haemodialysis, intravenou ...201626894074
draft genome sequence of mycobacterium tuberculosis kt-0184, isolated in south korea.here, we describe the draft genome sequence of mycobacterium tuberculosis kt-0184, from the beijing family. this genome will provide insight into the evolution and adaptation of m. tuberculosis kt-0184 in human hosts.201626893431
sweet syndrome and disseminated mycobacterium tuberculosis infection. 201626891891
mycobacterium orygis-associated tuberculosis in free-ranging rhinoceros, nepal, 2015. 201626890310
bcg vaccination induces robust cd4+ t cell responses to mycobacterium tuberculosis complex-specific lipopeptides in guinea pigs.a new class of highly antigenic, mhc-ii-restricted mycobacterial lipopeptides that are recognized by cd4-positive t lymphocytes of mycobacterium tuberculosis-infected humans has recently been described. to investigate the relevance of this novel class of mycobacterial ags in the context of experimental bacille calmette-guérin (bcg) vaccination, ag-specific t cell responses to mycobacterial lipid and lipopeptide-enriched ag preparations were analyzed in immunized guinea pigs. lipid and lipopeptid ...201626889044
increased isolation of nontuberculous mycobacteria among tb suspects in northeastern, tanzania: public health and diagnostic implications for control programmes.non-tuberculous mycobacteria (ntm) are increasingly reported worldwide associated with human disease. defining the significance of ntm in settings with endemic tuberculosis (tb) requires the discrimination of ntm from tb in suspect patients. correct and timely identification of ntm will impact both therapy and epidemiology of tb and tb-like diseases. the present study aimed at determining the frequency and diversity of ntm among tb suspects in northeastern tanzania.201626887928
genome-wide characterization of monomeric transcriptional regulators in mycobacterium tuberculosis.gene transcription catalysed by rna polymerase is regulated by transcriptional regulators, which play central roles in the control of gene transcription in both eukaryotes and prokaryotes. in regulating gene transcription, many regulators form dimers that bind to dna with repeated motifs. however, some regulators function as monomers, but their mechanisms of gene expression control are largely uncharacterized. here we systematically characterized monomeric versus dimeric regulators in the tuberc ...201626887897
screening of antitubercular compound library identifies novel shikimate kinase inhibitors of mycobacterium tuberculosis.shikimate kinase of mycobacterium tuberculosis is involved in the biosynthesis of aromatic amino acids through shikimate pathway. the enzyme is essential for the survival of m. tuberculosis and is absent from mammals, thus providing an excellent opportunity for identifying new chemical entities to combat tuberculosis with a novel mechanism of action. in this study, an antitubercular library of 1000 compounds was screened against m. tuberculosis shikimate kinase (mtsk). this effort led to the ide ...201626887318
genome-wide de novo prediction of cis-regulatory binding sites in mycobacterium tuberculosis h37rv.the transcription regulatory system of mycobacterium tuberculosis (m. tb) remains incompletely understood. in this study, we have applied the egleclubs algorithm to a group of related prokaryotic genomes for de novo genome-wide prediction of cis-regulatory binding sites (crbss) in m. tb h37rv. the top 250 clusters from our prediction recovered 83.3% (50/60) of all known crbss in extracted inter-operonic sequences of this strain. we further demonstrated that the integration of our prediction resu ...201626886880
a common variant in the adaptor mal regulates interferon gamma signaling.humans that are heterozygous for the common s180l polymorphism in the toll-like receptor (tlr) adaptor mal (encoded by tirap) are protected from a number of infectious diseases, including tuberculosis (tb), whereas those homozygous for the allele are at increased risk. the reason for this difference in susceptibility is not clear. we report that mal has a tlr-independent role in interferon-gamma (ifn-γ) receptor signaling. mal-dependent ifn-γ receptor (ifngr) signaling led to mitogen-activated p ...201626885859
global progress and challenges in implementing new medications for treating multidrug-resistant tuberculosis.two new drugs-bedaquiline and delamanid-have recently been approved by stringent regulatory authorities to treat multidrug-resistant tuberculosis (tb) and recommended by the world health organization for use under defined programmatic conditions. introducing the medications in tb programs worldwide has not kept pace with the need for these drugs. in response, the dr-tb stat (drug-resistant tb scale-up treatment action team) task force was formed in april 2015 to monitor progress and help overcom ...201626885674
identification of novel rd1 antigens and their combinations for diagnosis of sputum smear-/culture+ tb patients.rapid and accurate diagnosis of pulmonary tuberculosis (ptb) is an unresolved problem worldwide, especially for sputum smear- (s-) cases. in this study, five antigen genes including rv3871, rv3874, rv3875, rv3876, and rv3879 were cloned from mycobacterium tuberculosis (mtb) rd1 and overexpressed to generate antigen fragments. these antigens and their combinations were investigated for ptb serodiagnosis. 298 serum samples were collected from active ptb patients, including 117 sputum smear+ (s+) a ...201626885516
mass spectrometry offers insight into the role of ser/thr/tyr phosphorylation in the mycobacteria.phosphorylation is a post translational modification which can rapidly regulate biochemical pathways by altering protein function, and has been associated with pathogenicity in bacteria. once engulfed by host macrophages, pathogenic bacteria are exposed to harsh conditions and must respond rapidly in order to survive. the causative agent of tb, mycobacterium tuberculosis, is unusual amongst the bacteria because it can survive within the host macrophage for decades in a latent state, demonstratin ...201626904014
adenylate kinase: a novel antigen for immunodiagnosis and subunit vaccine against tuberculosis.mycobacterium tuberculosis (m.tb)-derived antigens capable of inducing strong cellular and/or humoral responses are potential targets for both immunodiagnosis and vaccine development against tuberculosis (tb). in the present study, we identified adenylate kinase (adk, rv0733) as an antigen that induces high cellular and antibody responses in active tb patients. we consequently tested the use of adk-specific t cells and antibodies as biomarkers for tb diagnosis. the adk-specific ifn-γ-producing c ...201626903285
statin adjunctive therapy shortens the duration of tb treatment in mice.the repurposing of existing agents may accelerate tb drug development. recently, we reported that the lipid-lowering drug simvastatin, when added to the first-line antitubercular regimen, reduces the lung bacillary burden in chronically infected mice.201626903278
neutrophils in tuberculosis--first line of defence or booster of disease and targets for host-directed therapy?necrotizing granulomas, exacerbating pathogenesis and neutrophil influx at the site of infection are hallmarks of active pulmonary tuberculosis (tb) in humans. the role of polymorphonuclear neutrophils (pmn) in host defence and tb pathogenesis has recently attracted broader interest. association of infiltrating pmn, enhanced mycobacterial load and disease exacerbation in both, mice susceptible to experimental tb as well as in tb patients, link pmn to exacerbated pathology. targeting pmn resulted ...201626903072
a flow cytometry method for rapidly assessing mycobacterium tuberculosis responses to antibiotics with different modes of action.current methods for assessing the drug susceptibility of mycobacterium tuberculosis are lengthy and do not capture information about viable organisms that are not immediately culturable under standard laboratory conditions as a result of antibiotic exposure. we have developed a rapid dual-fluorescence flow cytometry method using markers for cell viability and death. we show that the fluorescent marker calcein violet with an acetoxy-methyl ester group (cv-am) can differentiate between populations ...201626902767
compensatory mutations of rifampin resistance are associated with transmission of multidrug-resistant mycobacterium tuberculosis beijing genotype strains in china.mycobacterium tuberculosis can acquire resistance to rifampin (rif) through mutations in the rpob gene. this is usually accompanied by a fitness cost, which, however, can be mitigated by secondary mutations in the rpoa or rpoc gene. this study aimed to identify rpoa and rpoc mutations in clinical m. tuberculosis isolates in northern china in order to clarify their role in the transmission of drug-resistant tuberculosis (tb). the study collection included 332 rif-resistant and 178 rif-susceptible ...201626902762
pe11, a pe/ppe family protein of mycobacterium tuberculosis is involved in cell wall remodeling and virulence.the role of the unique proline-glutamic acid (pe)/proline-proline-glutamic acid (ppe) family of proteins in the pathophysiology and virulence of mycobacterium tuberculosis is not clearly understood. one of the pe family proteins, pe11 (lipx or rv1169c), specific to pathogenic mycobacteria is found to be over-expressed during infection of macrophages and in active tb patients. in this study, we report that m. smegmatis expressing pe11 (msmeg-pe11) exhibited altered colony morphology and cell wall ...201626902658
design and synthesis of 1-((1,5-bis(4-chlorophenyl)-2-methyl-1h-pyrrol-3-yl)methyl)-4-methylpiperazine (bm212) and n-adamantan-2-yl-n'-((e)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (sq109) pyrrole hybrid derivatives: discovery of potent antitubercular agents effective against multidrug-resistant mycobacteria.novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. the pyrroles have originally been designed as hybrids of the antitubercular drugs bm212 (1) and sq109 (2), which showed common chemical features with very similar topological distribution. a perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole c3 side chain and the removal of the c5 ary ...201626907951
extensively drug-resistant tuberculosis: principles of resistance, diagnosis, and management.extensively drug-resistant (xdr) tuberculosis (tb) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. although new drug developments have enabled tb to be more readily curable, inappropriate tb management has led to the emergence of drug-resistant disease. extensively drug-resistant tb describes mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. it proliferates when es ...201626906649
understanding dissemination of mycobacterium tuberculosis from the lungs during primary infection.understanding how inhaled m. tuberculosis achieves dramatic replication and crosses the alveolar barrier to establish systemic latent infection before adaptive immunity is elicited in humans, is limited by the small infecting inoculum carried in aerosol droplets (1-5 m diameter) and the inability to identify time of infection. m. tuberculosis is believed to disseminate via infected macrophages. however, like other invasive bacterial pathogens, m. tuberculosis could also cross the barrier direct ...201626905324
genetic features of mycobacterium tuberculosis modern beijing sublineage.mycobacterium tuberculosis (mtb) beijing strains have caused a great concern because of their rapid emergence and increasing prevalence in worldwide regions. great efforts have been made to investigate the pathogenic characteristics of beijing strains such as hypervirulence, drug resistance and favoring transmission. phylogenetically, mtb beijing family was divided into modern and ancient sublineages. modern beijing strains displayed enhanced virulence and higher prevalence when compared with an ...201626905026
development of a disaggregation-induced emission probe for the detection of reca inteins from mycobacterium tuberculosis.a fluorescent sensor - inr - with disaggregation-induced emission (die) characteristics has been developed for the label free detection of reca inteins from mycobacterium tuberculosis. mechanistic studies demonstrate that inr binds at a hydrophobic pocket of reca inteins, which is constituted by gly435, glu434, arg405 and arg 7, resulting in the disaggregation and recovery of its fluorescence.201626923771
recombination in pe/ppe genes contributes to genetic variation in mycobacterium tuberculosis lineages.approximately 10% of the mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high gc content and highly repetitive nature. the pe and ppe families are typified by their highly conserved n-terminal domains that incorporate proline-glutamate (pe) and proline-proline-glutamate (ppe) signature motifs. they are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and com ...201626923687
structures of eccb1 and eccd1 from the core complex of the mycobacterial esx-1 type vii secretion system.the esx-1 type vii secretion system is an important determinant of virulence in pathogenic mycobacteria, including mycobacterium tuberculosis. this complicated molecular machine secretes folded proteins through the mycobacterial cell envelope to subvert the host immune response. despite its important role in disease very little is known about the molecular architecture of the esx-1 secretion system.201626922638
[unilateral to bilateral pleurisy: pleural tuberculosis?].pleural tuberculosis is the first or second most common form of extrapulmonary tuberculosis as well as the main cause of pleural effusion in many countries. it is rare in young infants and is more common in children over 10 years of age. we report the case of a 19-month-old girl admitted for prolonged fever with unilateral pleural effusion. the mother reported a history of lymph node tuberculosis 6 years previously. intravenous antibiotics with cefotaxime and vancomycin were started. thoracocent ...201626922570
evaluation of anti-tubercular activity of linolenic acid and conjugated-linoleic acid as effective inhibitors against mycobacterium tuberculosis.to evaluate a new pharmacological activity/effect of linolenic acid (α- and γ-form) and conjugated-linoleic acid (cla) causing antibacterial activity against mycobacterium tuberculosis (mtb).201626919940
ion channel blockers as antimicrobial agents, efflux inhibitors, and enhancers of macrophage killing activity against drug resistant mycobacterium tuberculosis.given the ability of m. tuberculosis to survive as an intracellular pathogen and its propensity to develop resistance to the existing antituberculosis drugs, its treatment requires new approaches. here the antimycobacterial properties of verapamil, thioridazine, chlorpromazine, flupenthixol and haloperidol were investigated against a panel of drug resistant m. tuberculosis strains, both in vitro and on human-infected macrophages. these compounds are efflux inhibitors that share among them the ch ...201626919135
bioaerosol production by patients with tuberculosis during normal tidal breathing: implications for transmission risk.the size and concentration of exhaled bioaerosols may influence tb transmission risk. this study piloted bioaerosol measurement in patients with tb and assessed variability in bioaerosol production during normal tidal breathing. understanding this may provide a tool for assessing heterogeneity in infectivity and may inform mathematical models of tb control practices and policies.201626917579
whole genome sequencing to complement tuberculosis drug resistance surveys in uganda.understanding the circulating mycobacterium tuberculosis resistance mutations is vital for better tb control strategies, especially to inform a new mdr-tb treatment programme. we complemented the phenotypic drug susceptibility testing (dst) based drug resistance surveys (drss) conducted in uganda between 2008 and 2011 with whole genome sequencing (wgs) of 90 mycobacterium tuberculosis isolates phenotypically resistant to rifampicin and/or isoniazid to better understand the extent of drug resista ...201626917365
cohort for tuberculosis research by the indo-us medical partnership (ctriumph): protocol for a multicentric prospective observational study.tuberculosis disease (tb) remains an important global health threat. an evidence-based response, tailored to local disease epidemiology in high-burden countries, is key to controlling the global tb epidemic. reliable surrogate biomarkers that predict key active disease and latent tb infection outcomes are vital to advancing clinical research necessary to 'end tb'. well executed longitudinal studies strengthening local research capacity for addressing tb research priorities and advancing biomarke ...201626916698
understanding hiv-mycobacteria synergism through comparative proteomics of intra-phagosomal mycobacteria during mono- and hiv co-infection.mycobacterium tuberculosis (mtb) is the most common co-infection in hiv patients and a serious co-epidemic. apart from increasing the risk of reactivation of latent tuberculosis (tb), hiv infection also permits opportunistic infection of environmental non-pathogenic mycobacteria. to gain insights into mycobacterial survival inside host macrophages and identify mycobacterial proteins or processes that influence hiv propagation during co-infection, we employed proteomics approach to identify diffe ...201626916387
granzyme b as a diagnostic marker of tuberculosis in patients with and without hiv coinfection.immunodiagnostic tests for tuberculosis (tb) are based on the estimation of interferon γ (ifn-γ) or ifn-γ-secreting cd4(+) t cells following ex vivo stimulation with esat6 and cfp-10. sensitivity of these tests is likely to be compromised in cd4(+) t-cell-depleted situations, like hiv-tb coinfection. cd4(+) and cd8(+) t cells, isolated from 3 groups, viz., hiv-negative patients with active tb, hiv-tb coinfected patients, and healthy household contacts (hhcs) were cocultivated with autologous den ...201626915636
oxygen modulates the effectiveness of granuloma mediated host response to mycobacterium tuberculosis: a multiscale computational biology approach.mycobacterium tuberculosis associated granuloma formation can be viewed as a structural immune response that can contain and halt the spread of the pathogen. in several mammalian hosts, including non-human primates, mtb granulomas are often hypoxic, although this has not been observed in wild type murine infection models. while a presumed consequence, the structural contribution of the granuloma to oxygen limitation and the concomitant impact on mtb metabolic viability and persistence remains to ...201626913242
one episode of self-resolving plasmodium yoelii infection transiently exacerbates chronic mycobacterium tuberculosis infection.malaria and tuberculosis (tb) are two of the main causes of death from infectious diseases globally. the pathogenic agents, plasmodium parasites and mycobacterium tuberculosis, are co-endemic in many regions in the world, however, compared to other co-infections like hiv/tb or helminth/tb, malaria/tb has been given less attention both in clinical and immunological studies. due to the lack of sufficient human data, the impact of malaria on tb and vice versa is difficult to estimate but co-infecti ...201626913029
direct susceptibility testing of mycobacterium tuberculosis for pyrazinamide by use of the bactec mgit 960 system.pyrazinamide (pza) is a key antituberculosis drug, yet no rapid susceptibility test is commercially available. pza drug susceptibility testing (dst) was performed directly on sputum samples from 327 patients and compared with the indirect method by using the bactec mgit 960 system in the context of patient screening for participation in a drug trial. compared to standard indirect pza dst, direct dst was successful in only 59% of cases, but results obtained were highly accurate and available fast ...201626912751
methodological and clinical aspects of the molecular epidemiology of mycobacterium tuberculosis and other mycobacteria.molecular typing has revolutionized epidemiological studies of infectious diseases, including those of a mycobacterial etiology. with the advent of fingerprinting techniques, many traditional concepts regarding transmission, infectivity, or pathogenicity of mycobacterial bacilli have been revisited, and their conventional interpretations have been challenged. since the mid-1990s, when the first typing methods were introduced, a plethora of other modalities have been proposed. so-called molecular ...201626912567
the transcriptional foundations of sp110-mediated macrophage (raw264.7) resistance to mycobacterium tuberculosis h37ra.human tuberculosis (tb), caused by mycobacterium tuberculosis (mtb), remains a leading global health problem, causing 1.3 million deaths each year. the nuclear body protein, sp110, has been linked to tb resistance and previous work showed that it enhances macrophage apoptosis upon mtb infection. here, we report on the role of sp110 in transcriptional regulation of macrophage responses to mtb through integrated transcriptome and mechanistic studies. transcriptome analysis revealed that sp110 regu ...201626912204
early ifn-γ production together with decreased expression of tlr3 and tlr9 characterizes eae development conditional on the presence of myelin.experimental autoimmune encephalomyelitis (eae) is a model for the study of multiple sclerosis, which is an inflammatory and demyelinating disease of the central nervous system (cns). despite increased efforts to elucidate the function of toll-like receptors (tlrs) in autoimmune diseases of the cns, the relative contribution of other factors, including the immunomodulatory properties of tlr signaling, role of the innate response and the presence or absence of myelin peptides remain unclear. the ...201626911613
genetic determinants of drug resistance in mycobacterium tuberculosis and their diagnostic value.the development of molecular diagnostics that detect both the presence of mycobacterium tuberculosis in clinical samples and drug resistance-conferring mutations promises to revolutionize patient care and interrupt transmission by ensuring early diagnosis. however, these tools require the identification of genetic determinants of resistance to the full range of antituberculosis drugs.201626910495
study of mortality from infectious diseases in brazil from 2005 to 2010: risks involved in handling corpses.in the wake of disasters, the lack of information on how to handle and dispose of corpses leads the professionals involved in emergency operations to uncertainty about associated risks and safety precautions. the article seeks to establish the risks of the etiologic agents involved in brazilian mortality due to infectious diseases and identify and discuss the main protection measures for professionals involved in handling of corpses in disaster situations. it involved a survey of deaths by infec ...201626910156
a 1-year-old with mycobacterium tuberculosis endocarditis with mass spectrometry analysis of cardiac vegetation composition.in this study, we report the first case of mycobacterium tuberculosis endocarditis in an immunocompetent child born in the united states. mass spectrometry of the vegetation identified coagulation, humoral immune proteins, neutrophil granule proteins, and histones. few neutrophils on histopathology suggest that neutrophil extracellular traps may contribute to tuberculous endocardiac mass formation.201626908495
expression of the innate immune receptor lilrb5 on monocytes is associated with mycobacteria exposure.antigen presenting cells (apc) are critical components of innate immunity and consequently shape the adaptive response. leukocyte ig like receptors (lilr) are innate immune receptors predominantly expressed on myeloid cells. lilr can influence the antigen presenting phenotype of monocytic cells to determine the nature of t cell responses in infections including mycobaterium leprae. we therefore investigated the relevance of lilr in the context of mycobacterium tuberculosis. real-time pcr studies ...201626908331
characterization of mycobacterium tuberculosis isolates from hebei, china: genotypes and drug susceptibility phenotypes.tuberculosis remains a major public health problem in china. the hebei province is located in the beijing-tianjin-hebei integration region; however little information about the genetic diversity of mycobacterium tuberculosis was available in this area. this study describes the first attempt to map the molecular epidemiology of mtb strains isolated from hebei.201626939531
miru-vntr genotyping of mycobacterium tuberculosis strains using qiaxcel technology: a multicentre evaluation study.molecular genotyping of m.tuberculosis is an important laboratory tool in the context of emerging drug resistant tb. the standard 24-loci miru-vntr typing includes pcr amplification followed by the detection and sizing of pcr fragments using capillary electrophoresis on automated sequencers or using agarose gels. the qiaxcel advanced system might offer a cost-effective medium-throughput alternative.201626939051
identifying likely transmission pathways within a 10-year community outbreak of tuberculosis by high-depth whole genome sequencing.improved tuberculosis control and the need to contain the spread of drug-resistant strains provide a strong rationale for exploring tuberculosis transmission dynamics at the population level. whole-genome sequencing provides optimal strain resolution, facilitating detailed mapping of potential transmission pathways.201626938641
routes of synthesis of carbapenems for optimizing both the inactivation of l,d-transpeptidase ldtmt1 of mycobacterium tuberculosis and the stability toward hydrolysis by β-lactamase blac.combinations of β-lactams of the carbapenem class, such as meropenem, with clavulanate, a β-lactamase inhibitor, are being evaluated for the treatment of drug-resistant tuberculosis. however, carbapenems approved for human use have never been optimized for inactivation of the unusual β-lactam targets of mycobacterium tuberculosis or for escaping to hydrolysis by broad-spectrum β-lactamase blac. here, we report three routes of synthesis for modification of the two side chains carried by the β-lac ...201626937999
generation and characterization of bovine bone marrow-derived macrophage cell line.macrophages, as the forefront of innate immune defense, have an important role in the host responses to mycobacterial infection. therefore, a stable macrophage cell line is needed for future bovine immune system research on the bacterial infection. in this study, we established a bovine macrophage cell line by introducing the human telomerase reverse transcriptase (htert) gene into bovine bone marrow-derived macrophages (bbmms). the tert-bbmms cells expressed macrophage surface antigen (cd11b, c ...201626936441
an efficient and rapid method for enrichment of lipophilic proteins from mycobacterium tuberculosis h37rv for two-dimensional gel electrophoresis.lipophilic proteome profiling is crucial because they have an anticipated role in biological processes and pathogenesis of mycobacterium tuberculosis. these lipophilic proteins might be used as potential targets for the development of newer diagnostic markers and drug targets due to their association with membranes and drugs. we developed an efficient and rapid method to enrich the lipophilic proteins extraction from m. tuberculosis h37rv for 2de. in the extraction of lipophilic proteins, nonion ...201626935602
genotype mtbdrplus assay for rapid detection of multidrug resistance in mycobacterium tuberculosis: a meta-analysis.there is an urgent demand for rapid and accurate drug-susceptibility testing for the detection of multidrug-resistant tuberculosis. the genotype mtbdrplus assay is a promising molecular kit designed for rapid identification of resistance to first-line anti-tuberculosis drugs, isoniazid and rifampicin. the aim of this meta-analysis was to evaluate the diagnostic accuracy of genotype mtbdrplus in detecting drug resistance to isoniazid and rifampicin in comparison with the conventional drug suscept ...201626934724
mononuclear phagocyte accumulates a stearic acid derivative during differentiation into macrophages. effects of stearic acid on macrophage differentiation and mycobacterium tuberculosis control.the fatty acid composition of monocytes changes substantially during differentiation into macrophages, increasing the proportion of saturated fatty acids. these changes prompted us to investigate whether fatty acid accumulation in the extracellular milieu could affect the differentiation of bystander mononuclear phagocytes. an esterified fatty acid derivative, stearate, was the only fatty acid that significantly increased in macrophage supernatants, and there were higher levels when cells differ ...201626932544
innate myeloid cell tnfr1 mediates first line defence against primary mycobacterium tuberculosis infection.tnf is crucial for controlling mycobacterium tuberculosis infection and understanding how will help immunomodulating the host response. here we assessed the contribution of tnfr1 pathway from innate myeloid versus t cells. we first established the prominent role of tnfr1 in haematopoietic cells for controlling m. tuberculosis in tnfr1 ko chimera mice. further, absence of tnfr1 specifically on myeloid cells (m-tnfr1 ko) recapitulated the uncontrolled m. tuberculosis infection seen in fully tnfr1 ...201626931771
mechanisms of phenotypic rifampicin tolerance in mycobacterium tuberculosis beijing genotype strain b0/w148 revealed by proteomics.the "successful" russian clone b0/w148 of mycobacterium tuberculosis beijing is well-known for its capacity to develop antibiotic resistance. during treatment, resistant mutants can occur that have inheritable resistance to specific antibiotics. next to mutations, m. tuberculosis has several mechanisms that increase their tolerance to a variety of antibiotics. insights in the phenotypic mechanisms that contribute to drug tolerance will increase our understanding of how antibiotic resistance deve ...201626930559
simultaneous drug resistance detection and genotyping of mycobacterium tuberculosis using a low-density hydrogel microarray.nucleic acid amplification tests are widely used in tb diagnostics. priority tasks in their development consist of increasing the specificity and sensitivity of the detection of resistance to a wide spectrum of anti-tb drugs.201626929267
comparing isogenic strains of beijing genotype mycobacterium tuberculosis after acquisition of isoniazid resistance: a proteomics approach.we determined differences in the protein abundance among two isogenic strains of mycobacterium tuberculosis (mtb) with different isoniazid (inh) susceptibility profiles. the strains were isolated from a pulmonary tuberculosis patient before and after drug treatment. lc-ms/ms analysis identified 46 mtb proteins with altered abundance after inh resistance acquisition. protein abundance comparisons were done evaluating the different bacterial cellular fractions (membrane, cytosol, cell wall and sec ...201626929115
correction: classtr: classifying within-host heterogeneity based on tandem repeats with application to mycobacterium tuberculosis infections. 201626928849
pseudotumoral form of soft-tissue tuberculosis of the wrist.tuberculosis is a major public health problem in developing countries. hand and wrist is a rare localization for extra-pulmonary tuberculosis, a pseudotumoral form of soft tissue tuberculosis of the wrist is exceptional. we report the case of a 45-year-old male presenting with a painful swelling of the dorsal aspect of the right wrist evolving for six months. clinical study was evoking a ganglion cyst of the wrist. intraoperatively a pseudotumoral mass with rice bodies was found, suggesting tube ...201626927998
use of an adipocyte model to study the transcriptional adaptation of mycobacterium tuberculosis to store and degrade host fat.during its persistence in the infected host, mycobacterium tuberculosis (mtb) accumulates host-derived fatty acids in intracytoplasmic lipid inclusions as triacylglycerols which serve primarily as carbon and energy reserves. the mtb genome codes for more than 15 triacylglycerol synthases, 24 lipase/esterases, and seven cutinase-like proteins. hence, we looked at the expression of the corresponding genes in intracellular bacilli persisting amidst the host triacylglycerols. we used the mtb infecte ...201626927997
interaction of antimicrobial peptide with mycolyl transferase in mycobacterium tuberculosis.it is estimated that about 40% of the indian population are infected with tuberculosis (tb) and that ∼3,000,000 people die as a result of tb annually. tb is caused by mycobacterium tuberculosis. in 2011, the world health organization declared india as having the highest tb burden worldwide. an important criteria for pathogenicity is the presence of mycolic acid linked to the protective outer membrane of bacteria. mycolyl transferase catalyzes the transfer of mycolic acid and promotes cell wall s ...201626927995
genetic diversity of mycobacterium tuberculosis complex strains isolated from patients with pulmonary tuberculosis in anambra state, nigeria.in this study, we analyzed mycobacterium tuberculosis complex (mtc) genetic diversity in anambra state, nigeria based on spoligotyping followed by 5-loci exact tandem repeats (etrs). spoligotyping of 180 mtc strains isolated in 2009-2011 from pulmonary tuberculosis (tb) patients led to a total of 31 distinct patterns. a comparison with the sitvit2 international database showed that all the 31 patterns could be classified as shared-types (sits) in this database; briefly, 26/31 sits (n=174 isolate ...201626927993
populations of latent mycobacterium tuberculosis lack a cell wall: isolation, visualization, and whole-genome characterization.mycobacterium tuberculosis (mtb) causes active tuberculosis (tb) in only a small percentage of infected people. in most cases, the infection is clinically latent, where bacilli can persist in human hosts for years without causing disease. surprisingly, the biology of such persister cells is largely unknown. this study describes the isolation, identification, and whole-genome sequencing (wgs) of latent tb bacilli after 782days (26months) of latency (the ability of mtb bacilli to lie persistent).201626927992
analysis of the dosr regulon genes to select cytotoxic t lymphocyte epitope specific vaccine candidates using a reverse vaccinology approach.there is an urgent need for a more effective vaccine against mycobacterium tuberculosis (mtb). although cd4+ t cells play a central role in host immunity to mtb, recent evidence suggests a critical role of cd8+ t cells in combating mtb. in the present study, we have predicted hla antigen class i binding peptides of dosr operon using an in-silico approach. this method is useful as an initial computational filtration of probable epitopes based on their binding ability and antigenicity.201626927988
interferon-gamma release assays and tuberculin skin testing for diagnosing latent mycobacterium tuberculosis infection in at-risk groups in poland.the diagnostics of latent tuberculosis infection in poland using the tuberculin skin test is challenging due to the obligatory bacillus calmette-guérin vaccinations. interferon-gamma release assays are still very rarely used for diagnostics. we compared the tuberculin skin test and the quantiferon-tb gold in-tube test to evaluate the degree of latent tuberculosis infection in at-risk groups for tuberculosis (homeless, close contacts, periodic contacts, nursing-home attendees) and in healthy indi ...201626927987
correlating rrs and eis promoter mutations in clinical isolates of mycobacterium tuberculosis with phenotypic susceptibility levels to the second-line injectables.the in vitro drug-susceptibility testing of mycobacterium tuberculosis reports isolates as resistant or susceptible on the basis of single critical concentrations. it is evident that drug resistance in m. tuberculosis is quite heterogeneous, and involves low level, moderate level, and high level of drug-resistant phenotypes. thus, the aim of our study was to correlate rrs (x52917) and eis (af144099) promoter mutations, found in m. tuberculosis isolates, with corresponding minimum inhibitory conc ...201626927983
hiv skews the lineage-defining transcriptional profile of mycobacterium tuberculosis-specific cd4+ t cells.hiv-infected persons are at greater risk of developing tuberculosis (tb) even before profound cd4 loss occurs, suggesting that hiv alters cd4(+) t cell functions capable of containing bacterial replication. an effective immune response to mycobacterium tuberculosis most likely relies on the development of a balanced cd4 response, in which distinct cd4(+) th subsets act in synergy to control the infection. to define the diversity of m. tuberculosis-specific cd4(+) th subsets and determine whether ...201626927799
effect of vitamin d3 on chemokine levels and regulatory t-cells in pulmonary tuberculosis.1,25-dihydroxyvitamin d3 [1,25(oh)2d3] the active form of vitamin d3 acts as an immunomodulator in various immune cells. the present study is aimed to study the effect of 1,25(oh)2d3 on chemokine levels and regulatory t-cells in 51 healthy controls (hcs) and 50 pulmonary tuberculosis (ptb) patients. peripheral blood mononuclear cells were cultured with culture filtrate antigen (cfa) of mycobacterium tuberculosis in the presence or absence of 1,25(oh)2d3 at 10(-7) m concentration for 72 h and the ...201626927615
mycobacterium tuberculosis: manipulator of protective immunity.mycobacterium tuberculosis (mtb) is one of the most successful pathogens in human history and remains a global health challenge. mtb has evolved a plethora of strategies to evade the immune response sufficiently to survive within the macrophage in a bacterial-immunological equilibrium, yet causes sufficient immunopathology to facilitate its transmission. this review highlights mtb as the driver of disease pathogenesis and presents evidence of the mechanisms by which mtb manipulates the protectiv ...201626927066
susceptibility testing of antibiotics that degrade faster than the doubling time of slow-growing mycobacteria: ertapenem sterilizing effect versus mycobacterium tuberculosis.drug susceptibility tests (dsts) for mycobacterium tuberculosis require at least 7 days of incubation. drugs that are unstable at 37°c, such as ertapenem, are likely to be degraded before killing or inhibiting slow-growing bacteria. this would alter the mics of these drugs, including ertapenem, leading to falsely high mics. here, we describe a new strategy we developed to perform dsts and measure mics for such unstable compounds.201626926650
clofazimine contributes sustained antimicrobial activity after treatment cessation in a mouse model of tuberculosis chemotherapy.experimental and clinical studies have indicated that the antileprosy drug clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. clofazimine accumulates to high levels in tissues, has a long half-life, and remains in the body for months after administration is stopped. we hypothesized that in tuberculosis treatment, accumulated clofazimine may contribute sustained antimicrobial activity after treatment cessation, and we used the balb/c mouse m ...201626926638
whole-genome sequence of a beijing extensively drug-resistant mycobacterium tuberculosis clinical isolate from buenaventura, colombia.extensively drug-resistant mycobacterium tuberculosis (xdr-tb) has been reported to the who by 100 countries, including colombia. an estimated 9.0% of people with multidrug-resistant tb have xdr-tb. we report the genome sequence of a beijing xdr-tb clinical isolate from buenaventura, colombia. the genome sequence is composed of 4,298,162 bp with 4,359 genes.201626769935
tubercular osteomyelitis of the lateral-third of the clavicle.an elderly women with a chronic history of pain and swelling of the right clavicle was investigated. she also had constitutional symptoms. clinical examination showed mild inflammatory signs over the lateral one-third of the clavicle and the swelling was hard. clavicle x-ray showed a lytic lesion in the lateral-third of the clavicle and mri revealed a focal hyperintense area with cortical breach involving the superior cortex of the clavicle. the diagnosis was confirmed as tubercular osteomyeliti ...201626768706
within-host heterogeneity of mycobacterium tuberculosis infection is associated with poor early treatment response: a prospective cohort study.the clinical management of tuberculosis is a major challenge in southern africa. the prevalence of within-host genetically heterogeneous mycobacterium tuberculosis infection and its effect on treatment response are not well understood. we enrolled 500 patients with tuberculosis in kwazulu-natal and followed them through 2 months of treatment. using mycobacterial interspersed repetitive units-variable number of tandem repeats genotyping to identify mycobacterial heterogeneity, we report the preva ...201626768249
lipoprotein lpqs deficient m. tuberculosis mutant is attenuated for virulence in vivo and shows protective efficacy better than bcg in guinea pigs.bacterial lipoproteins are a functionally diverse class of membrane anchored proteins. lipoproteins constitute nearly 2.5% of the mycobacterium tuberculosis proteome. inactivation of genes coding for individual lipoproteins results in attenuated phenotype of the mutants. lpqs is a lipoprotein highly conserved among slow growing pathogenic mycobacteria. our previous study has shown that the lpqs gene deletion mutant of m. tuberculosis (mtbδlpqs) poorly replicates in thp1-(human acute monocytic le ...201626768127
a genome-wide association study of pulmonary tuberculosis in morocco.although epidemiological evidence suggests a human genetic basis of pulmonary tuberculosis (ptb) susceptibility, the identification of specific genes and alleles influencing ptb risk has proven to be difficult. previous genome-wide association (gwa) studies have identified only three novel loci with modest effect sizes in sub-saharan african and russian populations. we performed a gwa study of 550,352 autosomal snps in a family-based discovery moroccan sample (on the full population and on the s ...201626767831
rapid and specific diagnosis of extrapulmonary tuberculosis by immunostaining of tissues and aspirates with anti-mpt64.extrapulmonary tuberculosis (eptb) constitutes about 15% to 20% of all cases of tuberculosis (tb). the confirmation of eptb has always been a challenge to laboratory personnel. we aim to evaluate the diagnostic potential of immunostaining with anti-mpt64 in various eptb specimens.201626766121
antigen export reduces antigen presentation and limits t cell control of m. tuberculosis.persistence of mycobacterium tuberculosis results from bacterial strategies that manipulate host adaptive immune responses. infected dendritic cells (dcs) transport m. tuberculosis to local lymph nodes but activate cd4 t cells poorly, suggesting bacterial manipulation of antigen presentation. however, m. tuberculosis antigens are also exported from infected dcs and taken up and presented by uninfected dcs, possibly overcoming this blockade of antigen presentation by infected cells. here we show ...201626764596
evaluation of xpert mtb/rif for detection of mycobacterium tuberculosis in cerebrospinal fluid.studies investigating xpert mtb/rif diagnostic performance on cerebrospinal fluid (csf) samples are lacking in resource-rich settings. xpert mtb/rif results for 740 csf samples from 698 patients across england were retrospectively compared with the results of culture of the same and contemporary samples. the overall sensitivity was calculated at 55%.201626763963
gyrase mutations are associated with variable levels of fluoroquinolone resistance in mycobacterium tuberculosis.molecular diagnostics that rapidly and accurately predict resistance to fluoroquinolone drugs and especially later-generation agents promise to improve treatment outcomes for patients with multidrug-resistant tuberculosis and prevent the spread of disease. mutations in the gyr genes are known to confer most fluoroquinolone resistance, but knowledge about the effects of gyr mutations on susceptibility to early- versus later-generation fluoroquinolones and about the role of mutation-mutation inter ...201626763957
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