Global Markets Directs, Mycobacterium tuberculosis Protein Ag85A - Pipeline Review, H2 2016, provides in depth analysis on Mycobacterium tuberculosis Protein Ag85A targeted pipeline therapeutics.. The report provides comprehensive information on the Mycobacterium tuberculosis Protein Ag85A, targeted therapeutics, complete with analysis by indications, stage of development, mechanism of action (MoA), route of administration (RoA) and molecule type. The report also covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. Additionally, the report provides an overview of key players involved in Mycobacterium tuberculosis Protein Ag85A targeted therapeutics development and features dormant and discontinued projects.. Access Full Report with TOC @ http://www.radiantinsights.com/research/mycobacterium-tuberculosis-protein-ag85a-pipeline-review-h2-2016. Global Markets Directs report features investigational ...
Beijing strains are speculated to have a selective advantage over other Mycobacterium tuberculosis strains because of increased transmissibility and virulence. In Alberta, a province of Canada that receives a large number of immigrants, we conducted a population-based study to determine whether Beijing strains were associated with increased transmission leading to disease compared with non-Beijing strains. Beijing strains accounted for 258 (19%) of 1,379 pulmonary tuberculosis cases in 1991-2007; overall, 21% of Beijing cases and 37% of non-Beijing cases were associated with transmission clusters. Beijing index cases had significantly fewer secondary cases within 2 years than did non-Beijing cases, but this difference disappeared after adjustment for demographic characteristics, infectiousness, and M. tuberculosis lineage. In a province that has effective tuberculosis control, transmission of Beijing strains posed no more of a public health threat than did non-Beijing strains ...
TY - JOUR. T1 - Modeling Host-Pathogen Interaction to Elucidate the Metabolic Drug Response of Intracellular Mycobacterium tuberculosis. AU - Rienksma, Rienk A.. AU - Schaap, Peter J.. AU - Martins Dos Santos, Vitor A.P.. AU - Suarez-Diez, Maria. PY - 2019/5/8. Y1 - 2019/5/8. N2 - Little is known about the metabolic state of Mycobacterium tuberculosis (Mtb) inside the phagosome, a compartment inside phagocytes for killing pathogens and other foreign substances. We have developed a combined model of Mtb and human metabolism, sMtb-RECON and used this model to predict the metabolic state of Mtb during infection of the host. Amino acids are predicted to be used for energy production as well as biomass formation. Subsequently we assessed the effect of increasing dosages of drugs targeting metabolism on the metabolic state of the pathogen and predict resulting metabolic adaptations and flux rerouting through various pathways. In particular, the TCA cycle becomes more important upon drug application, ...
HIV coinfection is the greatest risk factor for transition of latent Mycobacterium tuberculosis infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of M. tuberculosis-specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. M. tuberculosis-specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)-T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV-M. tuberculosis-infected (coinfected) human DCs can dysregulate the M. tuberculosis-specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control M. tuberculosis infection in macrophages. After coculture with coinfected DCs, M. tuberculosis Ag-specific CD4 T cells lost their ability to enhance control of M. ...
Purified Recombinant Mycobacterium Tuberculosis ADK Protein (1-181 aa), His-SUMO-tagged from Creative Biomart. Recombinant Mycobacterium Tuberculosis ADK Protein (1-181 aa), His-SUMO-tagged can be used for research.
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Tuberculosis (TB) is a disease caused by a bacterium called Mycobacterium tuberculosis. The bacteria usually attack the lungs, but TB bacteria can attack any part of the body such as the kidney, spine, and brain. Tuberculous arthritis caused by Mycobacterium tuberculosis also has been described. The joints most frequently involved are the spine, hips, knees, wrists, and ankles. Valvular endocarditis due to Mycobacterium tuberculosis also has been reported. If not treated properly, TB disease can be fatal. VetPCR TBC Detection Kit is the direct detection of Mycobacterium tuberculosis on the basis of a genetic database, so it can diagnose very fast and accurately. It can amplify only specific gene using the PCR (Polymerase Chain Reaction) method, and take only 3 hours for detection. Therefore, it is a very fast, accurate and reliable technique.
To determine differences in the ability of Mycobacterium tuberculosis strains to withstand antituberculosis drug treatment, we compared the activity of antituberculosis drugs against susceptible Beijing and East-African/Indian genotype M. tuberculosis strains. Beijing genotype strains showed high rates of mutation within a wide range of drug concentrations, possibly explaining this genotypes association with multidrug-resistant tuberculosis.
Advantages of sSNP genotyping: sSNPs afford many advantages for analysis of phylogenetic relationships among microbial strains, especially closely related clonal organisms such as the M. tuberculosis complex. Most or all sSNPs are selectively neutral and hence minimally subject to convergence, a process that can obscure or distort evolutionary relationships (Kimura 1983). Binary data are obtained, which means that the information is readily amenable to storage, retrieval, analysis by personal computers equipped with simple software, and comparison between different laboratories and studies. Importantly, the considerable biomedical interest in human SNPs (Schorket al. 2000; Dalyet al. 2001; Gut 2001; Johnsonet al. 2001) means that microbial pathogen research will benefit extensively from the ongoing development and implementation of methods to index very large numbers of SNPs efficiently, inexpensively, and automatically (Kwok 2001). Because of the many advantages of using sSNP analysis for ...
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Background: The risk of encountering tuberculosis (TB) has reduced with the decreased incidence of the disease; however, it still can be found at autopsy.. Aim: To assess the magnitude of exposure to Mycobacterium tuberculosis at autopsy in a large general hospital setting, in a country with low incidence.. Methods: Retrospective search of the autopsy records from 1991 to 2004. Patients records and histological slides were reviewed, and medical personnel interviewed.. Results: 15 cases of active TB were identified in the 14-year period, during which 4930 autopsies were performed (1 case per 329 autopsies); of these, 10 cases were unsuspected (67%). Five of these cases contained abundant acid-fast bacilli. Patients tended to be middle aged and males with complex clinical histories; two were HIV positive. Two patients were brought in dead to hospital, with no clinical indication of TB. Of 15 autopsy staff, 1 required chemoprophylaxis but none contracted TB.. Conclusion: The risk of unexpectedly ...
Early detection of resistance to second-line anti-tuberculosis drugs is important for the management of multidrug-resistant (MDR)-TB. The Genotype® MTBDRsl VERSION 2.0 (VER 2.0) line probe assay has been redesigned for molecular detection of resistance-conferring mutations of fluoroquinolones (FLQ) (gyrA and gyrB genes) and second-line injectable drugs (SLID) (rrs and eis genes). The study evaluated the diagnostic performance of MTBDRsl VER 2.0 for the detection of second-line drug resistance compared with phenotypic drug susceptibility testing (DST), using the Bactec™ MGIT 960 system on Mycobacterium tuberculosis complex isolates from South Africa. A total of 268 repository isolates collected between 2012 and 2014, with rifampicin -mono-resistant (RR) or MDR based on DST were selected. MTBDRsl VER 2.0 testing was performed on these isolates and results analysed. The MTBDRsl VER 2.0 sensitivity and specificity indices for culture isolates were; FLQ 100% (95% CI, 95.8-100%) ; 98.9% (95% CI, ...
PhD Project - Protein kinases and nitric oxide in the stealthy survival of Mycobacterium tuberculosis at University of Leicester, listed on FindAPhD.com
Signs of Mycobacterium Tuberculosis, Susceptibility to, X-linked including medical signs and symptoms of Mycobacterium Tuberculosis, Susceptibility to, X-linked, symptoms, misdiagnosis, tests, common medical issues, duration, and the correct diagnosis for Mycobacterium Tuberculosis, Susceptibility to, X-linked signs or Mycobacterium Tuberculosis, Susceptibility to, X-linked symptoms.
Mycobacterium tuberculosis (Mtb) and helminth infections elicit antagonistic immune effector functions and are co-endemic in several regions of the world. We therefore hypothesized that helminth infection may influence Mtb-specific T-cell immune responses. We evaluated the cytokine profile of Mtb-specific T cells in 72 individuals with pulmonary TB disease recruited from two Sub-Saharan regions with high and moderate helminth burden i.e. 55 from Tanzania (TZ) and 17 from South Africa (SA), respectively. We showed that Mtb-specific CD4 T-cell functional profile of TB patients from Tanzania are primarily composed of polyfunctional Th1 and Th2 cells, associated with increased expression of Gata-3 and reduced expression of T-bet in memory CD4 T cells. In contrast, the cytokine profile of Mtb-specific CD4 T cells of TB patients from SA was dominated by single IFN-γ and dual IFN-γ/TNF-α and associated with TB-induced systemic inflammation and elevated serum levels of type I IFNs. Of note, the ...
BioAssay record AID 1084878 submitted by ChEMBL: Antitubercular activity against multidrug-resistant Mycobacterium tuberculosis by NCCLS agar dilution method.
BioAssay record AID 245416 submitted by ChEMBL: Minimum inhibitory concentration against resistant Mycobacterium tuberculosis clinical isolates; N=9; Range=8-16.
Mycobacterium tuberculosis ATCC ® 25177D-5™ Designation: Genomic DNA from Mycobacterium tuberculosis Strain H37Ra TypeStrain=False Application: Respiratory research
Metabolomics and stable isotope labelling studies of virulent Mycobacterium tuberculosis reveal a de-centralised metabolic network able to utilise various amino acids as nitrogen sources to a better extent than ammonium.
3550 NIEMANN ET AL. J. CLIN. MICROBIOL. 5. Cohen, T., and M. Murray. 2004. Modeling epidemics of multidrug-resistant 23. Mokrousov, I., T. Otten, B. Vyshnevskiy, and O. Narvskaya. 2002. Detection Mycobacterium tuberculosis of heterogeneous !tness. Nat. Med. 10:1117- of embB306 mutations in ethambutol-susceptible clinical isolates of Myco- 1121. bacterium tuberculosis from Northwestern Russia: implications for genotypic 6. Comas, I., S. Homolka, S. Niemann, and S. Gagneux. 2009. Genotyping of resistance testing. J. Clin. Microbiol. 40:3810-3813. genetically monomorphic bacteria: DNA sequencing in mycobacterium tu- 24. Mokrousov, I., T. Otten, T. Zozio, E. Turkin, V. Nazemtseva, A. Sheremet, B. berculosis highlights the limitations of current methodologies. PLoS One Vishnevsky, O. Narvskaya, and N. Rastogi. 2009. At Baltic crossroads: a 4:e7815. molecular snapshot of Mycobacterium tuberculosis population diversity in 7. Cox, H. S., S. Kalon, S. Allamuratova, V. Sizaire, Z. N. Tigay, S. Rusch- ...
BACKGROUND: Peru holds the fourth highest burden of tuberculosis in the Americas. Despite an apparently well-functioning DOTS control program, the prevalence of multidrug resistant tuberculosis (MDR-TB) continues to increase. To worsen this situation, cases of extensively drug resistance tuberculosis (XDR-TB) have been detected. Little information exists about the genetic diversity of drug-susceptible vs. MDR-TB and XDR-TB. METHODS: Cryopreserved samples of XDR strains from 2007 to 2009 (second semester), were identified and collected. Starting from 227 frozen samples, a total of 142 XDR-TB strains of Mycobacterium tuberculosis complex (MTBC; 1 isolate per patient) were retained for this study. Each strain DNA was analyzed by spoligotyping and the 15-loci Mycobacterial Interspersed Repetitive Unit (MIRU-15). RESULTS: Among the 142 isolates analyzed, only 2 samples (1.41%) could not be matched to any lineage. The most prevalent sublineage was Haarlem (43.66%), followed by T (27.46%), LAM (16.2%),
Spontaneous phthiocerol dimycocerosate-deficient variants of Mycobacterium tuberculosis are susceptible to gamma interferon-mediated immunity Academic Article ...
Rapid and accurate detection of Mycobacterium tuberculosis complex (MTBc) is a key aspect of effective tuberculosis treatment and control. The Amplified Mycobacterium tuberculosis complex Direct Test (Gen-Probe) utilizes transcription mediated amplification to detect MTB complex ribosomal RNA. This test is very sensitive, specific, and can be performed within 5 hours. Although it does not differentiate among members of the MTB complex, i.e., M. tuberculosis, M. bovis, M. bovis BCG, M africanum, and M. microti , the isolation of the last 4 organisms is very rare.. The test is currently approved by FDA for AFB smear-positive respiratory specimens from untreated patients (sensitivity = 98%, specificity = 96.8%). However, studies have shown that it will also benefit patients with high suspicion of tuberculosis, but with negative AFB smear results. A positive result is strongly suggestive for the diagnosis of tuberculosis if the clinical history and radiographic finding are consistent. This test ...
Abstract. Tobacco use is a major risk factor for tuberculosis (TB). Secondhand smoke (SHS) is also a risk factor for TB and to a lesser extent, Mycobacterium tuberculosis infection without disease. We investigated the added risk of M. tuberculosis infection due to SHS exposure in childhood contacts of TB cases in The Gambia. Participants were childhood household contacts aged ≤ 14 years of newly diagnosed pulmonary TB (PTB) cases. The intensity of exposure to the case was categorized according to whether contacts slept in the same room, same house, or a different house as the case. Contacts were tested with an enzyme-linked immunospot interferon gamma release assay. In multivariate regression models, M. tuberculosis infection was associated with increasing exposure to a case (odds ratios [OR]: 3.9, 95% confidence interval [CI]: 2.11-71.4, P | 0.001]) and with male gender (OR: 1.5 [95% CI: 1.12-2.11], P = 0.008). Tobacco use caused a 3-fold increase in the odds of M. tuberculosis infection in children
Worldwide, there are nearly 10 million new cases of active TB and 1.8 million associated deaths every year. WHO estimates that one-third of the worlds population is infected with Mycobacterium tuberculosis (Mtb), forming a huge latent Mtb global reservoir. This renders the prospect of ever eliminating Mtb from the human race almost impossible. Several controversial issues regarding host-pathogen interactions and existing prevention and eradication strategies for latent Mtb infections need to be critically re-examined. In this viewpoint, widely held assumptions on Mtb latency and isoniazid monotherapy and chemoprophylaxis are challenged. We highlight the need for future research to resolve these issues and to develop evidence-based strategies for better understanding of equilibrium and escape of Mtb in the human body, eventually leading to global recommendations for elimination of the latent Mtb state through informed policy and practice. Until such strategies and policies are realized, WHO and ...
Pulmonary and pleural fibrosis is one of pathological characterized by Mycobacterium tuberculosis (M. tb) infection in the lungs. When the lungs are infected with M. tb, the recruitment of immune cells and fibroblasts leads to granuloma formation and fibrotic scaring in interstitial lung tissue, which in turns causes irreversible loss of pulmonary function and pulmonary failure. Several studies indicated that the fibrotic factors, such as transforming growth factor- (TGF-), were increased in pleural effusion and serum of patient with tuberculosis. The expression of connective tissue growth factor (CTGF), a fibrotic factor, has been reported in lung fibrosis. However, the mechanism of M. tb-induced CTGF expression in human lung fibroblasts is still unclear. Fibrocytes are unique bone marrow-derived mesenchymal progenitor cells found in circulation. Fibrocytes have been shown to play an important role in wound healing following injury and in the generation of pulmonary fibrosis. Previous ...
One third of the global population is estimated to be latently infected with Mycobacterium tuberculosis We performed a phase I randomized controlled trial of isoniazid preventive therapy (IPT) before revaccination with bacillus Calmette-Guérin (BCG) in healthy, tuberculin skin test-positive (≥15-mm induration), HIV-negative South African adults. We hypothesized that preclearance of latent bacilli with IPT modulates BCG immunogenicity following revaccination. Frequencies and coexpression of IFN-γ, TNF-α, IL-2, IL-17, and/or IL-22 in CD4 T cells and IFN-γ-expressing CD8 T, γδ T, CD3(+)CD56(+) NKT-like, and NK cells in response to BCG were measured using whole blood intracellular cytokine staining and flow cytometry. We analyzed 72 participants who were revaccinated with BCG after IPT (n = 33) or without prior IPT (n = 39). IPT had little effect on frequencies or cytokine coexpression patterns of M. tuberculosis- or BCG-specific responses. Revaccination transiently boosted BCG-specific Th1 ...
In 1947 Dubos and Middlebrook formulated a media (7H9) containing albumin and oleic acid which enhanced the growth of tubercle bacilli, and protected the organisms against a variety of toxic agents. (5) Later, in 1958, Middlebrook and Cohn improved this first formulation and developed a media (7H10) which allowed more luxuriant, faster growth of Mycobacterium species. (9) Cohn, in 1968, incorporated casein hydrolysate into the 7H10 medium, and obtained a media that stimulated the growth of mycobacteria that would not otherwise grow on the 7H10 medium. This formulation was then designated 7H11 Agar, and is recommended over 7H10 Agar. (4,7) Middlebrook 7H11 Agar contains inorganic compounds that supply essential growth stimulating inorganic salts as well as vitamins and necessary co-factors. Glycerol is provided as a source of carbon and energy for the tubercle organisms. Sodium citrate is converted to citric acid, which holds the inorganic cations in solution. Casein hydrolysate is incorporated ...
HIV coinfection is the greatest risk factor for transition of latent Mycobacterium tuberculosis infection into active tuberculosis (TB). Epidemiological data reveal both the reduction and the impairment of M. tuberculosis-specific CD4 T cells, although the cellular link and actual mechanisms resulting in immune impairment/suppression need further characterization. M. tuberculosis-specific CD4 T cells play a central role in development of protective immunity against TB, in which they participate in the activation of macrophages through the dendritic cell (DC)-T cell axis. Using an in vitro priming system for generating Ag-specific T cells, we explored if HIV-M. tuberculosis-infected (coinfected) human DCs can dysregulate the M. tuberculosis-specific CD4 T cell phenotype and functionality and subsequently mediate the failure to control M. tuberculosis infection in macrophages. After coculture with coinfected DCs, M. tuberculosis Ag-specific CD4 T cells lost their ability to enhance control of M. ...
Author Summary Mycobacterium tuberculosis is one of the most life-threatening pathogens of all time, having infected one-third of the present human population. There is an urgent need for both novel vaccines and diagnostic strategies. Here, we were able to identify the targets most dominantly recognized by latently infected individual that successfully contain infection. These targets are contained in three broadly genomic antigenic islands, all related to bacterial secretion systems and composed by several distinct ORFs. Thus, our results suggest that vaccination with one or few defined antigens will fail to replicate the response associated with natural immunity. Our analysis also pinpoints that the Th1 cells dominating the response are associated with novel and well-defined phenotypic markers, suggesting that the response is molded by unique MTB associated factors. This study demonstrates further that the approach combining peptide binding predictions with modern high throughput techniques is
TY - JOUR. T1 - Proficiency of drug susceptibility testing for Mycobacterium tuberculosis in Taiwan. AU - Jou, Ruwen. AU - Chiang, C. Y.. AU - Yu, C. Y.. AU - Wu, M. H.. PY - 2009/9. Y1 - 2009/9. N2 - OBJECTIVE: To evaluate the impact of external quality assessment on the quality of drug susceptibility testing (DST) in clinical mycobacteriology laboratories. DESIGN: A pilot evaluation of DST proficiency was conducted in 2006 and scaled up in 2007. A panel consisting of 20 Mycobacterium tuberculosis isolates was used. Accuracy of 95% in detecting resistance to both isoniazid (INH) and rifampicin (RMP), and 90% to both ethambutol (EMB) and streptomycin (SM), was used to define a competent laboratory. RESULTS: Nine laboratories participated in 2006 and 30 in 2007. In 2006, the mean accuracy in detecting resistance to INH was 91.6%, for RMP it was 96.1%, for EMB it was 90.5% and for SM it was 93.9%. In 2007, the mean accuracy in detecting resistance to INH increased to 95.7% and that for RMP to ...
Scherr N., Honnappa S., Kunz G., Mueller P., Jayachandran R., Winkler F., Pieters J., Steinmetz M.O.. The pathogenicity of mycobacteria such as Mycobacterium tuberculosis is closely associated with their capacity to survive within host macrophages. A crucial virulence factor for intracellular mycobacterial survival is protein kinase G (PknG), a eukaryotic-like serine/threonine protein kinase expressed by pathogenic mycobacteria that blocks the intracellular degradation of mycobacteria in lysosomes. Inhibition of PknG with the highly selective low-molecular-weight inhibitor AX20017 results in mycobacterial transfer to lysosomes and killing of the mycobacteria. Here, we report the 2.4 A x-ray crystal structure of PknG in complex with AX20017. The unique multidomain topology of PknG reveals a central kinase domain that is flanked by N- and C-terminal rubredoxin and tetratrico-peptide repeat domains, respectively. Directed mutagenesis suggests that the rubredoxin domain functions as a regulator of ...
TY - JOUR. T1 - Failure of a Mycobacterium tuberculosis ΔRD1 ΔpanCD double deletion mutant in a neonatal calf aerosol M. bovis challenge model. T2 - Comparisons to responses elicited by M. bovis bacille Calmette Guerin. AU - Waters, W. Ray. AU - Palmer, Mitchell V.. AU - Nonnecke, Brian J.. AU - Thacker, Tyler C.. AU - Scherer, Charles F Capinos. AU - Estes, D. Mark. AU - Jacobs, William R.. AU - Glatman-Freedman, Aharona. AU - Larsen, Michelle H.. PY - 2007/11/7. Y1 - 2007/11/7. N2 - An attenuated Mycobacterium tuberculosis RD1 knockout and pantothenate auxotroph (mc26030) vaccine administered at 2 weeks of age failed to protect calves from low dose, aerosol M. bovis challenge at 2.5 months of age. In contrast, M. bovis bacille Calmette Guerin (BCG)-vaccinates had reduced tuberculosis-associated pathology as compared to non- and mc26030-vaccinates. Mycobacterial colonization was not impacted by vaccination. Positive prognostic indicators associated with reduced pathology in the BCG-vaccinated ...
Scanning electron micrograph (SEM) of Mycobacterium tuberculosis, MDR-TB and XDR-TB strain, rod bacterium (prokaryote). Mycobacterium tuberculosis is the primary causative agent of human tuberculosis (TB). Contaminated respiratory secretions transmit the infection between humans. In the past few years drug resistant strains, MDR-TB and XDR-TB strains have emerged, especially in developing countries. MDR-TB (Multidrug Resistant TB) strains are resistant to at least the two first-line TB drugs, isoniazid and rifampicin. XDR-TB, or Extensive Drug Resistant TB (also known as Extreme Drug Resistance) is a strain that is also resistant to three or more of the six classes of second-line drugs. Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Magnification: x3,400 when shortest axis printed at 25 millimetres. - Stock Image C037/0132
IL-12, a cytokine produced by macrophages and B cells, has recently been found to exert pleiotropic effects on the immune system. When BALB/c mice, a strain highly susceptible to virulent Mycobacterium tuberculosis infection, were given IL-12 at the initiation of infection with M. tuberculosis, their mean survival time doubled from 58 to 112 days. IL-12-treated mice had diminished bacterial burdens, whereas treatment with exogenous IFN-gamma had no effect on survival or bacterial burden. IL-12 treatment also delayed lung pathology in BALB/c mice. In contrast with the findings in the BALB/c model, IL-12 did not increase survival of M. tuberculosis-infected gko mice, transgenic mice in which the IFN-gamma gene has been disrupted, indicating that IL-12 does not induce protection against tuberculosis in mice in the absence of IFN-gamma. ...
Mycobacterium tuberculosis, the primary agent of tuberculosis, must acquire iron from the host to cause infection. To do so, it releases high-affinity iron-binding siderophores called exochelins. Exochelins are thought to transfer iron to another type of high-affinity iron-binding molecule in the bacterial cell wall, mycobactins, for subsequent utilization by the bacterium. In this paper, we describe the purification of exochelins of M. tuberculosis and their characterization by mass spectrometry. Exochelins comprise a family of molecules whose most abundant species range in mass from 744 to 800 Da in the neutral Fe(3+)-loaded state. The molecules form two 14-Da-increment series, one saturated and the other unsaturated, with the increments reflecting different numbers of CH2 groups on a side chain. These series further subdivide into serine- or threonine-containing species. The virulent M. tuberculosis Erdman strain and the avirulent M. tuberculosis H37Ra strain produce a similar set of ...
Abstract: Approximately 1.7 billion population of the world contain latent Mycobacterium tuberculosis (Mtb) with a substantial risk of progression to clinical outcome. Containment of seed beds of Mtb is essential to eliminate tuberculosis completely in high burden settings like India. Hence, there is an urgent need for the development of putative serological markers for detection or vaccine candidates to prevent latent tuberculosis infection (LTBI). DosR regulon antigens of Mtb might serve as attractive targets for LTBI diagnosis or vaccine development as they are specifically expressed and are up-regulated during latent phase. In this study, we investigated the role of Rv2004c, a member of DosR regulon (exclusive to Mtb complex), in host pathogen interactions and its immunogenic potential in LTBI, active TB and healthy control cohorts. Rv2004c elicited strong antibody response in individuals with LTBI compared to active TB patients and healthy cohorts. Recombinant Rv2004c induced pro-inflammatory
Mycobacterium tuberculosis is an obligate aerobic acid resistant rod-shaped bacterium which causes most of the cases of tuberculosis. The term Mycobacterium tuberculosis complex includes closely related bacteria causing the same clinical symptoms - M. tuberculosis, M. bovis, M. africanum, M. microti and M. canetti. Tuberculosis still remains a serious infectious disease, namely because of the rising occurrence of antituberculosis drug resistance and because of the increasing proportion of immunocompromised individuals in the human population, although a sophisticated system of inoculation and prevention exists.. ...
Mycobacterium tuberculosis-induced cellular aggregation is essential for granuloma formation and may assist establishment and early spread of M. tuberculosis infection. The M. tuberculosis ESX1 mutant, which has a non-functional type VII secretion system, induced significantly less production of the host macrophage-derived chemokine fractalkine (CX3CL1). Upon infection of human macrophages ESX1-dependent fractalkine production mediated selective recruitment of CD11b+ monocytic cells and increased infection of neighbouring cells consistent with early local spread of infection. Fractalkine levels were raised in vivo at tuberculous disease sites in humans and were significantly associated with increased CD11b+ monocytic cellular recruitment and extent of granulomatous disease. These findings suggest a novel fractalkine-dependent ESX1-mediated mechanism in early tuberculous disease pathogenesis in humans. Modulation of M. tuberculosis-mediated fractalkine induction may represent a potential ...
TY - JOUR. T1 - Reduced virulence of an extensively drug-resistant outbreak strain of mycobacterium tuberculosis in a murine model. AU - Smith, Kristen L.Jurcic. AU - Saini, Divey. AU - Bardarov, Svetoslav. AU - Larsen, Michelle. AU - Frothingham, Richard. AU - Gandhi, Neel R.. AU - Jacobs, William R.. AU - Sturm, A. Willem. AU - Lee, Sunhee. PY - 2014/4/14. Y1 - 2014/4/14. N2 - Bacterial drug resistance is often associated with a fitness cost. Large outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have been described that predominately affect persons with HIV infection. We obtained four closely-related Mycobacterium tuberculosis strains (genotype F15/LAM4/KZN) from an outbreak in KwaZulu-Natal (KZN), South Africa, including drug-sensitive, MDR, and XDR clinical isolates. We compared the virulence of these strains in a murine model of aerosol M. tuberculosis infection for four phenotypes: (1) competitive in vivo growth in lung and spleen, (2) non-competitive in vivo ...
Species identification of isolates belonging to the Mycobacterium tuberculosis complex (MTC) seems to be important for the appropriate treatment of patients, since M. bovis is naturally resistant to a first line anti-tuberculosis (TB) drug, pyrazinamide, while most of the other MTC members are susceptible to this antimicrobial agent. A simple and low-cost differentiation method was needed in higher TB burden countries, such as Bangladesh, where the prevalence of M. bovis among people or cattle has not been investigated. Genetic regions cfp32, RD9 and RD12 were chosen as targets for a species distinguishable multiplex PCR and the system was evaluated with twenty reference strains of mycobacterial species including non-tubercular mycobacteria (NTM). A total of 350 clinical MTC isolates obtained in Bangladesh were then analyzed with this multiplex PCR. All of the MTC reference strains gave expected banding patterns and no non-specific amplifications were observed in the NTM strains. Out of 350 clinical
This study will examine how the immune system responds to infection with Mycobacterium tuberculosis bacteria (bacteria that cause tuberculosis) in order to better understand how the germ produces infection and how the immune response might work to control the infection.. Only about one in 10 people infected by M. tuberculosis become sick, sometimes years or even decades after exposure. It is not known why some people become sick and most do not, but the immune system of people who never develop disease may be better able to control the bacteria. This study will evaluate the latent form of M. tuberculosis infection to further the understanding of the immune mechanisms - particularly the role of certain white blood cells - involved in the disease process.. Healthy volunteers 18 years of age and older may be eligible for this study. Candidates are screened with a medical history, family history of medical conditions, sexual history, history of drug use, physical examination and blood tests, ...
This study will examine how the immune system responds to infection with Mycobacterium tuberculosis bacteria (bacteria that cause tuberculosis) in order to better understand how the germ produces infection and how the immune response might work to control the infection.. Only about one in 10 people infected by M. tuberculosis become sick, sometimes years or even decades after exposure. It is not known why some people become sick and most do not, but the immune system of people who never develop disease may be better able to control the bacteria. This study will evaluate the latent form of M. tuberculosis infection to further the understanding of the immune mechanisms - particularly the role of certain white blood cells - involved in the disease process.. Healthy volunteers 18 years of age and older may be eligible for this study. Candidates are screened with a medical history, family history of medical conditions, sexual history, history of drug use, physical examination and blood tests, ...
SILVA, Joas Lucas da et al. Plasmid-based controls to detect rpoB mutations in Mycobacterium tuberculosis by quantitative polymerase chain reaction-high-resolution melting. Mem. Inst. Oswaldo Cruz [online]. 2013, vol.108, n.1, pp.106-109. ISSN 0074-0276. https://doi.org/10.1590/S0074-02762013000100017.. Quantitative polymerase chain reaction-high-resolution melting (qPCR-HRM) analysis was used to screen for mutations related to drug resistance in Mycobacterium tuberculosis. We detected the C526T and C531T mutations in the rifampicin resistance-determining region (RRDR) of the rpoB gene with qPCR-HRM using plasmid-based controls. A segment of the RRDR region from M. tuberculosis H37Rv and from strains carrying C531T or C526T mutations in the rpoB were cloned into pGEM-T vector and these vectors were used as controls in the qPCR-HRM analysis of 54 M. tuberculosis strains. The results were confirmed by DNA sequencing and showed that recombinant plasmids can replace genomic DNA as controls in the ...
Mouse monoclonal antibody raised against recombinant Mycobacterium tuberculosis 16 KDa Ag. Recombinant protein corresponding to Mycobacterium tuberculosis 16 kDa Ag. (MAB3166) - Products - Abnova
TY - JOUR. T1 - Human β-defensin 2 is expressed and associated with Mycobacterium tuberculosis during infection of human alveolar epithelial cells. AU - Rivas-Santiago, Bruno. AU - Schwander, Stephan K.. AU - Sarabia, Carmen. AU - Diamond, Gill. AU - Klein-Patel, Marcia E.. AU - Hernandez-Pando, Rogelio. AU - Ellner, Jerrold J.. AU - Sada, Eduardo. PY - 2005/8. Y1 - 2005/8. N2 - To determine the role of human β-defensin 2 (HBD-2) in human tuberculosis, we studied the in vitro induction of HBD-2 gene expression by Mycobacterium tuberculosis H37Rv infection in the human lung epithelial cell line A549, in alveolar macrophages (AM), and in blood monocytes (MN) by reverse transcription-PCR. We also studied the induction of HBD-2 gene expression by mannose lipoarabinomannan (manLAM) from M. tuberculosis. Intracellular production of HBD-2 peptide was detected by immunocytochemistry and electron microscopy. Our results demonstrated that there was induction of HBD-2 mRNA in A549 cells after infection ...
DTH (delayed type hypersensitivity) reactions are secondary cellular immune responses that appear 24-72 h after antigen exposure. Tuberculous pleurisy is a common manifestation of extrapulmonary TB (tuberculosis) and is considered a human model of Th1-mediated DTH. In order to identify functional cross-talk among cellular populations sited in this inflammatory microenvironment, we analysed phenotypic and functional features of human B-cells isolated from the PF (pleural fluid) of TB patients. Freshly isolated PF-B-cells displayed a lower expression of CD20, CD1d and HLA-DR, and a higher expression of CD95, CD38, CD25, CXCR3 (CXC chemokine receptor 3) and CXCR4 (CXC chemokine receptor 4) than their PB (peripheral blood) counterparts, suggesting a non-classical in situ activation. Although memory PF-T-cell frequencies were increased, the frequencies of memory PF-B-cells were not. We demonstrated that, upon stimulation with γ-irradiated M. tuberculosis, mycobacterially secreted proteins or a ...
Strains of the Beijing/W genotype family of Mycobacterium tuberculosis have caused large outbreaks of tuberculosis, sometimes involving multidrug resistance. This genetically highly conserved family of M. tuberculosis strains predominates in some geographic areas. We have conducted a systematic review of the published reports on these strains to determine their worldwide distribution, spread, and association with drug resistance. Sixteen studies reported prevalence of Beijing strains defined by spoligotyping; another 10 used other definitions. Beijing strains were most prevalent in Asia but were found worldwide. Associations with drug resistance varied: in New York, Cuba, Estonia, and Vietnam, Beijing strains were strongly associated with drug resistance, but elsewhere the association was weak or absent. Although few reports have measured trends in prevalence, the ubiquity of the Beijing strains and their frequent association with outbreaks and drug resistance underline their importance.
A major challenge for the development of an effective vaccine against tuberculosis (TB) is that the attributes of protective CD4+ T cell responses are still elusive for human TB. Infection with HIV type 1 is a major risk factor for TB, and a better understanding of HIV-induced alterations of Mycobacterium tuberculosis-specific CD4+ T cells that leads to failed host resistance may provide insight into protective T cell immunity to TB. A total of 86 participants from a TB-endemic setting, either HIV-infected or uninfected and with latent or active TB (aTB), were screened using M. tuberculosis-specific MHC class II tetramers. We examined the phenotype as well as function of ex vivo M. tuberculosis-specific tetramer+CD4+ T cells using flow cytometry. The numbers of M. tuberculosis-specific tetramer+CD4+ T cells were relatively well maintained in HIV-infected persons with aTB, despite severe immunodeficiency. However, although HIV-uninfected persons with latent TB infection exhibited ex vivo M. ...
Mycobacterium tuberculosis is an obligate human pathogen capable of persisting in individual hosts for decades. We sequenced the genomes of 21 strains representative of the global diversity and six major lineages of the M. tuberculosis complex (MTBC) at 40- to 90-fold coverage using Illumina next-generation DNA sequencing. We constructed a genome-wide phylogeny based on these genome sequences. Comparative analyses of the sequences showed, as expected, that essential genes in MTBC were more evolutionarily conserved than nonessential genes. Notably, however, most of the 491 experimentally confirmed human T cell epitopes showed little sequence variation and had a lower ratio of nonsynonymous to synonymous changes than seen in essential and nonessential genes. We confirmed these findings in an additional data set consisting of 16 antigens in 99 MTBC strains. These findings are consistent with strong purifying selection acting on these epitopes, implying that MTBC might benefit from recognition by ...
TY - JOUR. T1 - Early abnormalities of the antibody response against Mycobacterium tuberculosis in human immunodeficiency virus infection. AU - Saltini, Cesare. AU - Amicosante, Massimo. AU - Girardi, Enrico. AU - Antonucci, Giorgio. AU - Ippolito, Giuseppe. AU - Ameglio, Franco. AU - Monno, Laura. AU - Congedo, Pierpaolo. AU - Angarano, Gioacchino. AU - Babudieri, Sergio. AU - Guaraldi, Giovanni. AU - Visco, Giuseppe. AU - Piccolella, Enza. AU - Paone, Gregorino. AU - Pallotta, Giovanni. AU - Bisetti, Alberto. PY - 1993/12. Y1 - 1993/12. N2 - Among human immunodeficiency virus (HIV)-infected persons, those who react against purified protein derivative (PPD) have higher risk of tuberculosis. Since PPD testing has limited predictive power in HIV-positive populations, new markers of antituberculous immunity were sought by analyzing antibodies to Mycobacterium tuberculosis antigens (PPD and its fraction A60) in 102 HIV-positive subjects, some PPD-positive and some PPD-negative, and in 23 ...
The hypervirulent Mycobacterium tuberculosis strain HN878 induces a potent TH1 response followed by rapid down-regulation.: The HN878 strain of Mycobacterium tu
M. tuberculosis accesses the terminal lung and is phagocytosed by alveolar macrophages. Utilizing a mouse intratracheal challenge model, we demonstrate that M. tuberculosis rapidly enters through M cells as well. From there, bacilli are deposited within associated intraepithelial leukocytes and subs …
TY - JOUR. T1 - Salicylate uniquely induces a 27-kDa protein in tubercle bacillus. AU - Sun, Zhonghe. AU - Cheng, Shao Ji. AU - Zhang, Hao. AU - Zhang, Ying. PY - 2001/9/25. Y1 - 2001/9/25. N2 - Salicylate was found to uniquely induce a 27-kDa protein in Mycobacterium tuberculosis complex organisms but not in Mycobacterium smegmatis or Escherichia coli. The structural analogue antitubercular para-amino-salicylate also induced the 27-kDa protein but to a somewhat lower level than salicylate. Other structural analogues such as benzoic acid and acetyl salicylic acid (aspirin) did not induce the 27-kDa protein. Western blot analysis indicated that the 27-kDa protein was localized mainly in the cytoplasm. The 27-kDa protein was not expressed at different growth phases in the absence of salicylate. The 27-kDa protein was identified as a putative benzoquinone methyltransferase (Rv0560c), which has several homologues in the M. tuberculosis genome. The cloned 27-kDa gene was found to express ...
Jacob Baker, Graduate Student in Microbiology and Molecular Genetics, Michigan State University. Upon encountering the host-relevant environment of acidic pH, Mycobacterium tuberculosis (Mtb) slows and even arrests growth in a process that requires remodeling of central carbon metabolism. Acidic pH growth arrest is an active process that leads to stress and antibiotic tolerance, with genetic disruption of growth arrest increasing Mtb sensitivity to antibiotic treatment.. ...
Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.
Evaluation of Biochip System in Determining Isoniazid and Rifampicin Resistances of Mycobacterium Tuberculosis in Sputum Samples. Wei Lu; Cheng Chen; Yan Shao; Jinyan Shi; Chongqiao Zhong; Dandan Yang; Honghuan Song; Guoli Li; Xiaoyan Ding; Hong Peng; Linyang Zhu; Yang Zhou; Limei Zhu // PLoS ONE;Dec2012, Vol. 7 Issue 12, p1 Objective: To evaluate a biochip system in determining isoniazid and rifampicin resistances of Mycobacterium tuberculosis in sputum samples in a Chinese population. Methods: We assembled 907 sputum smeared positive specimens of tuberculosis patients in total. Each sample would be separated into... ...
Tuberculosis (TB) drug, regimen, and vaccine development rely heavily on preclinical animal experiments, and quantification of bacterial and immune response dynamics is essential for understanding drug and vaccine efficacy. A mechanism-based model was built to describe Mycobacterium tuberculosis H37Rv infection over time in BALB/c and athymic nude mice, which consisted of bacterial replication, bacterial death, and adaptive immune effects. The adaptive immune effect was best described by a sigmoidal function on both bacterial load and incubation time. Applications to demonstrate the utility of this baseline model showed (i) the important influence of the adaptive immune response on pyrazinamide (PZA) drug efficacy, (ii) a persistent adaptive immune effect in mice relapsing after chemotherapy cessation, and (iii) the protective effect of vaccines after M. tuberculosis challenge. These findings demonstrate the utility of our model for describing M. tuberculosis infection and corresponding adaptive ...
The causative agent of human tuberculosis (TB), Mycobacterium tuberculosis, is an obligate pathogen that evolved to exclusively persist in human populations. For M. tuberculosis to transmit from person to person, it has to cause pulmonary disease. Therefore, M. tuberculosis virulence has likely been a significant determinant of the association between M. tuberculosis and humans. Indeed, the evolutionary success of some M. tuberculosis genotypes seems at least partially attributable to their increased virulence. The latter possibly evolved as a consequence of human demographic expansions. If co-evolution occurred, humans would have counteracted to minimize the deleterious effects of M. tuberculosis virulence. The fact that human resistance to infection has a strong genetic basis is a likely consequence of such a counter-response. The genetic architecture underlying human resistance to M. tuberculosis remains largely elusive. However, interactions between human genetic polymorphisms and M. ...
We evaluated the clinical usefulness of spoligotyping, a polymerase chain reaction-based method for simultaneous detection and typing of Mycobacterium tuberculosis strains, with acid-fast bacilli-positive slides from clinical specimens or mycobacterial cultures. Overall sensitivity and specificity were 97% and 95% for the detection of M. tuberculosis and 98% and 96% when used with clinical specimens. Laboratory turnaround time of spoligotyping was less than that for culture identification by a median of 20 days. In comparison with IS6110-based restriction fragment length polymorphism typing, spoligotyping overestimated the number of isolates with identical DNA fingerprints by approximately 50%, but showed a 100% negative predictive value. Spoligotyping resulted in the modification of ongoing antimycobacterial treatment in 40 cases and appropriate therapy in the absence of cultures in 11 cases. The rapidity of this method in detection and typing could make it useful in the management of ...
The aim of the study was to investigate behavior of resistant Mycobacterium tuberculosis (MTB) isolates under a high dose of ofloxacin and its morphological changes. 19 extensively drug resistant (XDR) clinical isolates of MTB were grown on Löwenstein-Jensen medium containing progressively increasing concentrations of ofloxacin (2, 4, 8, 16, 32 mg/L). Ultra-structure analyses of resistant isolates grown on ofloxacin were conducted by transmission electron microscopy (TEM). Fixation was carried out by 4% glutaraldehyde in 0.1 M sodium cacodylate buffer on 300 mesh carbon formvar copper grid. The samples were negatively stained with uranium acetate suspension. All19XDRMTBisolatesweregrownandformedcoloniessuccessfullyon2,4,8mg/L,sevenisolates on16mg/L,andfourisolateson32mg/Lofloxacin. Morphologicalchangesandunusualformswere detected in 8, 16 and 32 mg/L ofloxacin at 43%, 76.5% and 81% of cells, respectively. Swollen form (protoplast like), ghost-like cell, degraded forms, and in a few cases, detached
Dormancy in non-sporulating bacteria is an interesting and underexplored phenomenon with significant medical implications. In particular, latent tuberculosis may result from the maintenance of Mycobacterium tuberculosis bacilli in non-replicating states in infected individuals. Uniquely, growth of M. tuberculosis in aerobic conditions in potassium-deficient media resulted in the generation of bacilli that were non-culturable (NC) on solid media but detectable in liquid media. These bacilli were morphologically distinct and tolerant to cell-wall-targeting antimicrobials. Bacterial counts on solid media quickly recovered after washing and incubating bacilli in fresh resuscitation media containing potassium. This resuscitation of growth occurred too quickly to be attributed to M. tuberculosis replication. Transcriptomic and proteomic profiling through adaptation to, and resuscitation from, this NC state revealed a switch to anaerobic respiration and a shift to lipid and amino acid metabolism. High ...
According to Worth Health Organization, tuberculosis claims about 2 million lives every year with almost one-third of the human population infected with M. tuberculosis, a microorganism that develops resistance to virtually all new drugs produced to fight it. Inadequate dosing and incomplete treatment regimens, together with the ability of the bacilli to cause latent infections that are tolerant of currently used drugs, have contributed to the rise of multidrug-resistant tuberculosis [1]. While intensive research efforts are addressing the pathogenesis, new drugs and vaccines are also necessary to explore into conceptual novel approaches for tuberculosis control. Studies of the role of M. tuberculosis molecules involved in host bacteria interactions identified a number of immunodominant mycobacterial proteins which undergo a process of posttranslational modifications such as glycosylation, lipoylation and methylation that provide important immunological properties [2-7]. Thus, these proteins are ...
Mycobacterium tuberculosis is an important pathogen of mammals that relies on 2-hydroxyphenyloxazoline-containing siderophore molecules called mycobactins for the acquisition of iron in the restrictive environment of the mammalian macrophage. These compounds have been proposed to be biosynthesized through the action of a cluster of genes that include both nonribosomal peptide synthase and polyketide synthase components. One of these genes encodes a protein, MbtB, that putatively couples activated salicylic acid with serine or threonine and then cyclizes this precursor to the phenyloxazoline ring system. We have used gene replacement through homologous recombination to delete the mbtB gene and replace this with a hygromycin-resistance cassette in the virulent strain of M. tuberculosis H37Rv. The resulting mutant is restricted for growth in iron-limited media but grows normally in iron-replete media. Analysis of siderophore production by this organism revealed that the biosynthesis of all salicylate
Mycobacterium tuberculosis 38 kDa antibody [5174] for ELISA, WB. Anti-Mycobacterium tuberculosis 38 kDa mAb (GTX36772). 100% Ab-Assurance.
TY - JOUR. T1 - A chemical proteomics approach to profiling the ATP-binding proteome of Mycobacterium tuberculosis. AU - Wolfe, Lisa M.. AU - Veeraraghavan, Usha. AU - Idicula-Thomas, Susan. AU - Schuerer, Stephan C. AU - Wennerberg, Krister. AU - Reynolds, Robert. AU - Besra, Gurdyal S.. AU - Dobos, Karen M.. PY - 2013/6/1. Y1 - 2013/6/1. N2 - Tuberculosis, caused by Mycobacterium tuberculosis, remains one of the leading causes of death worldwide despite extensive research, directly observed therapy using multidrug regimens, and the widespread use of a vaccine. The majority of patients harbor the bacterium in a state of metabolic dormancy. New drugs with novel modes of action are needed to target essential metabolic pathways in M. tuberculosis; ATP-competitive enzyme inhibitors are one such class. Previous screening efforts for ATP-competitive enzyme inhibitors identified several classes of lead compounds that demonstrated potent anti-mycobacterial efficacy as well as tolerable levels of ...
Introduction. Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium bovis BCG, Mycobacterium canettii, Mycobacterium africanum, Mycobacterium pinnipedii, Mycobacterium microti, Mycobacterium caprae, the dassie and the oryx bacillus, and the recently discovered Mycobacterium mungi are closely related species that form the M. tuberculosis complex (MTBC). Mycobacterium tuberculosis and M. bovis are the most important species in the complex which commonly cause human and animal tuberculosis (TB), with concomitant negative consequences for human and animal health and economic costs.. The probability of M. bovis transmission is more likely to occur between animals, particularly those in close contact such as herd animals (Grange & Collins 1987). Humans can also be infected by M. bovis from contact with infected animals or animal products and the likelihood of infection and disease, as with human forms of TB are exacerbated by crowding and stress (Figueroa-Munoz & Ramon-Pardo 2008). The ...
Introduction. Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium bovis BCG, Mycobacterium canettii, Mycobacterium africanum, Mycobacterium pinnipedii, Mycobacterium microti, Mycobacterium caprae, the dassie and the oryx bacillus, and the recently discovered Mycobacterium mungi are closely related species that form the M. tuberculosis complex (MTBC). Mycobacterium tuberculosis and M. bovis are the most important species in the complex which commonly cause human and animal tuberculosis (TB), with concomitant negative consequences for human and animal health and economic costs.. The probability of M. bovis transmission is more likely to occur between animals, particularly those in close contact such as herd animals (Grange & Collins 1987). Humans can also be infected by M. bovis from contact with infected animals or animal products and the likelihood of infection and disease, as with human forms of TB are exacerbated by crowding and stress (Figueroa-Munoz & Ramon-Pardo 2008). The ...
Mycobacterium tuberculosis (MTB) is a global heath epidemic, its threat amplified by HIV infection and the emergence of multidrug-resistant tuberculosis (MDR-TB). Interferon (IFN)-gamma release assays (IGRAs) have improved the accuracy of detection of MTB exposure in some subject groups as compared to the Tuberculin Skin Test (TST). However, as IFN-gamma is produced by both fully rested and more recently activated populations of memory T cells, it is not surprising that the measurement of this cytokine alone cannot accurately distinguish Latent TB Infected (LTBI) subjects from those with active (infectious) disease. Accurate and rapid diagnosis of infectious individuals would allow medication to be properly allocated and other actions taken to more effectively curtail MTB spread. Analysis of multi-cytokine profiles ex vivo after stimulation of PBMCs from LTBI and active MTB subjects indicate the real possibility of successfully discerning these two disease states within 24 hours of a subjects blood
The Mycobacterium tuberculosis complex CFP-10/ESAT-6 family proteins play essential but poorly defined roles in tuberculosis pathogenesis. In this article we report the results of detailed spectroscopic studies of several members of the CFP10/ESAT-6 family. This work shows that the CFP-10/ESAT-6 related proteins, Rv0287 and Rv0288, form a tight 1:1 complex, which is predominantly helical in structure and is predicted to closely resemble the complex formed by CFP-10 and ESAT-6. In addition, the Rv0287.Rv0288 complex was found to be significantly more stable to both chemical and temperature induced denaturation than CFP-10.ESAT-6. This approach demonstrated that neither Rv0287.Rv0288 nor the CFP-10.ESAT-6 complexes are destabilized at low pH (4.5), indicating that even in low pH environments, such as the mature phagosome, both Rv0287.Rv0288 and CFP-10.ESAT-6 undoubtedly function as complexes rather than individual proteins. Analysis of the structure of the CFP-10.ESAT-6 complex and optimized amino ...
Frédéric Veyrier obtained his M.Sc. degree from the INRS-Institut Armand Frappier Laval (Qc) on the metal homeostasis in different pathogens. He completed his PhD studies at McGill University, Montréal (Qc) on the evolution of the human pathogen Mycobacterium tuberculosis. He moved back to France in 2010 as a young researcher at the Institut Pasteur, Paris (France). His research focused on the common evolution of nasopharyngeal pathogens like Neisseria meningitidis, Haemophilus influenzae or Moraxella catarrhalis . Specifically, he is studying how bacterial metal transport and cell-wall have evolved to adjust to the stringent and competitive nasopharynx environment. He is now an associate professor at the INRS-Institut Armand Frappier in Canada continuing his work on human bacterial symbionts evolution.. Tweets by VeyrierFrederic ...
The completion of the genome sequence of Mycobacterium tuberculosis strain H37Rv revealed that 10% of the coding capacity is devoted to two, large multigene families that are characterised by repeat sequences. These are the PE and PPE families that code for acidic, glycine rich proteins. A subgroup of the PE family is the polymorphic GC rich sequence (PGRS) gene subfamily. Genome comparisons of clinical isolates of M. tuberculosis have confirmed the polymorphic character of some of these genes suggesting they may be analogous to the contingency loci found in other pathogenic bacteria. Certain PE-PGRS proteins play a direct role in virulence in M. marinum, other PE-PGRS genes are cell surface associated, and some PE-PGRS proteins are variable surface antigens, supporting a potential role in host pathogen interactions. A reporter assay designed to investigate mutations in a PE-PGRS repeat-containing sequence was used to assess mutation rates in various M. smegmatis host strains by fluctuation ...
Author: Jungblut, Peter R. et al.; Genre: Journal Article; Published in Print: 2001-09; Title: Proteomics reveals open reading frames in Mycobacterium tuberculosis H37Rv not predicted by genomics
Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 μM, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the divergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a ...
Isoniazid resistant Mycobacterium tuberculosis (Hr-TB) is the most frequently encountered TB resistance phenotype in North America but limited data exist on the...
Phthiocerol dimycocerosates (PDIM), glycolipids found on the outer surface of virulent members of the Mycobacterium tuberculosis (Mtb) complex, are a major contributing factor to the pathogenesis of Mtb. Myelocytic cells, such as macrophages and dendritic cells, are the primary hosts for Mtb after infection and previous studies have shown multiple roles for PDIM in supporting Mtb in these cells. However, Mtb can infect other cell types. We previously showed that Mtb efficiently replicates in human lymphatic endothelial cells (hLECs) and that the hLEC cytosol acts as a reservoir for Mtb in humans. Here, we examined the role of PDIM in Mtb translocation to the cytosol in hLECs. Analysis of a Mtb mutant unable to produce PDIM showed less co-localisation of bacteria with the membrane damage marker Galectin-8 (Gal8), indicating that PDIM strongly contribute to phagosomal membrane damage. Lack of this Mtb lipid also leads to a reduction in the proportion of Mtb co-localising with markers of macroautophagic
Using molecular typing, twenty-five percent of relapse cases (65; 25%) were clustered in 29 clusters. A retrospective studies revealed that patients in clusters developed their second episode of TB within the same period. Further analysis of spoligopatterns identified Haarlem I and Beijing types of M. tuberculosis strains in thirty eight percent of patients in clusters(38%)(table. 2). Therefore, the possibility of exogenous reinfection through transmission of particular M. tuberculosis strains were highlighted. Although, due to non-availability of previous culture genotyping results, we could not confirm the exogenous reinfection in them. Recently, investigators have suggested that the relative contribution of exogenous reinfection increases in parallel with the incidence of disease [6, 8, 18]. Most reported cases of exogenous reinfection observed among alcoholic residents of a homeless shelter or patients with advanced HIV infection [6, 9, 19]. We found no particular risk factors between ...
Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the ...
L-Aspartate a-decarboxylase (ADC) belongs to a class of pyruvoyl dependent enzymes and catalyzes the conversion of aspartate to ?-alanine in the pantothenate pathway, which is critical for the growth of several micro-organisms, including ,i,Mycobacterium tuberculosis ,/i,(Mtb). Its presence only in micro-organisms, fungi and plants and its absence in animals, particularly human, make it a promising drug target. Cleaved ,i,Mycobacterium tuberculosis ,/i, L-Aspartate a-decarboxylase (MtbADC) structure was modelled and based on chemoinformatics drug-design approach, potential drug-like inhibitors against MtbADC were identified, following which we employed proton Nuclear Magnetic Resonance (NMR) based assay to systematically screen the inhibitors that we have earlier identified from the Maybridge, National Cancer Institute (NCI) and Food and Drug Administration (FDA) approved drugs databases and those reported earlier in the literature(Sharma et al., PLoS ONE 7,e33521, 2012). The concentrations of ...
Tuberculosis, a major health problem in developing countries, has reemerged in recent years in many industrialized countries. The increased susceptibility of immunocompromised individuals to tuberculosis, and many experimental studies indicate that T cell-mediated immunity plays an important role in resistance. The lymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophage activation and resistance to intracellular pathogens. Mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection with Mycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactive nitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma. ...
Thanks to Turner et al for commenting on our article. Turner et al challenge our finding that the Bacillus Calmette-Guérin vaccine (BCG) can prevent Mycobacterium tuberculosis infection (MTI), and propose an alternative explanation: that the absence of a positive interferon gamma release assay (IGRA) could be due to antigenic sin and does not necessarily demonstrate absence of infection.. A positive IGRA is the best available surrogate for MTI, but we are fully aware of its limitations. With the IGRA test, MTI is defined by a T-cell-induced interferon gamma response to M tuberculosis antigens … ...
Mycobacterium tuberculosis adalah bakteri penyebab penyakit tuberkulosa.[1] Mycobacterium tuberculosis pertama kali dideskripsikan pada tanggal 24 Maret 1882 oleh Robert Koch. Bakteri ini juga disebut abasilus Koch. ...
Tuberculosis remains a worldwide threat despite the availability of the BCG vaccine and antibiotic treatment. It is estimated that its etiologic agent, Mycobacterium tuberculosis, infects almost a third of the human population and kills two million people every year (27). The recent human immunodeficiency virus pandemic, the selection of multidrug-resistant strains of M. tuberculosis, and the increased immigration from countries with a high tuberculosis incidence, coupled with increasing poverty and homelessness in these countries, have awakened the developed nations from the widespread apathy toward tuberculosis (36). Indeed, recent years have seen great progress in the molecular characterization of this efficient human pathogen (26, 61). However, much work is still needed to understand how M. tuberculosis copes with the numerous environments it encounters in the course of a successful infection. Adaptation to such conditions must require a complex regulation of gene expression.. The main ...
Heterologous prime-boost regimens are a valuable strategy to improve the generation of effector-memory T cell responses against intracellular pathogens. In this study we show that newborn mice vaccinated with bacillus Calmette-Guérin (BCG) and boosted with heparin-binding haemagglutinin (HBHA) had enhanced protective immunity against intranasal or aerosol Mycobacterium tuberculosis challenge over non-boosted mice, as evidenced by a considerable reduction of mycobacterial load in spleen and lung. The route of HBHA delivery had a differential impact on cytokine and antibody production in BCG-primed mice. The prime-boost regimen induced not only HBHA-specific IFN-gamma, but also other cytokines, such as IL-12 and TGF-beta, which may be associated with the generation of lung Th1 effector-memory lymphocytes, responsible for the enhanced protection against M. tuberculosis challenge.
Background. Tuberculosis (TB) is a serious public health problem in developing countries such as Pakistan. Rapid diagnosis of TB and detection of drug resistance are very important for timely and appropriate management of multidrug-resistant TB (MDR-TB). Objective. The purpose of this study was to determine the diagnostic efficacy of the Xpert MTB/RIF assay for rapid diagnosis of TB and detection of rifampicin (RIF) resistance in extrapulmonary and smear-negative pulmonary TB suspects. Methods. A total of 98 bronchoalveolar lavage fluid (BALF) and 168 extrapulmonary specimens were processed by Xpert MTB/RIF. Culture results are considered as the gold standard for diagnosis of TB, and drug susceptibility testing for detection of RIF resistance. Diagnostic efficacy was measured in terms of sensitivity, specificity and positive and negative predictive values. Results. The Xpert MTB/RIF assay detected 40 (40.8 %) of 98 BALF of presumptive pulmonary TB and 60 (35.7 %) of 168 extrapulmonary specimens.
The role of clonal complexity has gradually been accepted in infection by Mycobacterium tuberculosis (MTB), although analyses of this issue are limited. We performed an in-depth study of a case of recurrent MTB infection by integrating genotyping, whole genome sequencing, analysis of gene expression and infectivity in in vitro and in vivo models. Four different clonal variants were identified from independent intrapatient evolutionary branches. One of the single-nucleotide polymorphisms in the variants mapped in mce3R, which encodes a repressor of an operon involved in virulence, and affected expression of the operon. Competitive in vivo and in vitro co-infection assays revealed higher infective efficiency for one of the clonal variants. A new clonal variant, which had not been observed in the clinical isolates, emerged in the infection assays and showed higher fitness than its parental strain. The analysis of other patients involved in the same transmission cluster revealed new clonal variants acquired
Mycobacterium tuberculosis complex strains contain a unique chromosomal region, which consists of multiple 36bp direct repeats (DRs), which are interspersed by unique spacers 35 to 41 bp in length. In this study we investigated the nature of the DNA polymorphism of this DR cluster by sequencing part …
DNA fingerprinting is an important tool for tracking the spread and studying the global diversity of M. tuberculosis. With the increasing recognition of the importance of the Beijing genotype family in the worldwide TB epidemic (2, 10), the availability of a suitable typing method for this family, which can be used for large-scale typing, became a matter of utmost importance in the global control of TB. Due to its high resolution, simplicity, sensitivity, high reproducibility, and easy interlaboratory comparison (15, 18, 25), the 12-locus MIRU typing method has been found to be highly suitable for global epidemiological surveillance of TB. MIRU typing was even found to produce more distinct patterns than IS6110 RFLP and spoligotyping (1, 4). In 2002, following the adoption of an agreed International Standard Protocol, a consensus was reached in the European Union Concerted Action meeting, New Genetic Markers and Techniques for the Epidemiology and Control of Tuberculosis (Cascais, Portugal, ...
Taxon: Bacteria; Actinobacteria; Actinobacteridae; Actinomycetales; Corynebacterineae; Mycobacteriaceae; Mycobacterium; Mycobacterium tuberculosis ...
4PMN: Crystal structure of the Mycobacterium tuberculosis Tat-secreted protein Rv2525c in complex with MES (monoclinic crystal form I)
Rao, S.P.S., Rand, L., Dick, T., Pethe, K., Alonso, S. (2008). The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America 105 (33) : 11945-11950. [email protected] Repository. https://doi.org/10.1073/pnas. ...
A DNA amplification assay using the polymerase chain reaction technique designed for the rapid identification of Mycobacterium bovis organisms was used to test 211 human mycobacterial isolates and 177 clinical specimens previously submitted for routine mycobacterial culture. The procedures described could be used by routine or specialist laboratories for identification of M. tuberculosis complex organisms in 4 h and/or as a rapid screening method for the direct detection of M. tuberculosis complex organisms in specimens.. ...
In the search for effective vaccines against intracellular pathogens such as HIV, tuberculosis and malaria, recombinant viral vectors are increasingly being used to boost previously primed T cell responses. Published data have shown prime-boost vaccination with BCG-MVA85A (modified vaccinia virus Ankara expressing antigen 85A) to be highly immunogenic in humans as measured by ex vivo IFN-γ ELISPOT. Here, we used polychromatic flow cytometry to investigate the phenotypic and functional profile of these vaccine-induced Mycobacterium tuberculosis (M.tb) antigen 85A-specific responses in greater detail. Promisingly, antigen 85A-specific CD4 + T cells were found to be highly polyfunctional, producing IFN-γ TNF-α, IL-2 and MIP-1β. Surface staining showed the responding CD4 + T cells to be relatively immature (CD45RO + CD27 int CD57 - ); this observation was supported by the robust proliferative responses observed following antigenic stimulation. Furthermore, these phenotypic and functional
Tuberculosis remains one of the leading causes of morbidity and mortality worldwide. Therefore, understanding the pathophysiology of Mycobacterium tuberculosis is imperative for developing new drugs. Post-transcriptional regulation plays a significant role in microbial adaptation to different growth conditions. While the proteins associated with gene expression regulation have been extensively studied in the pathogenic strain M. tuberculosis H37Rv, post-transcriptional regulation involving small RNAs (sRNAs) remains poorly understood. We developed a novel moving-window based approach to detect sRNA expression using RNA-Seq data. Overlaying ChIP-seq data of RNAP (RNA Polymerase) and NusA suggest that these putative sRNA coding regions are significantly bound by the transcription machinery. Besides capturing many experimentally validated sRNAs, we observe the context-dependent expression of novel sRNAs in the intergenic regions of M. tuberculosis genome. For example, ncRv11806 shows expression only in the
Abstract Background Tuberculosis is one of the leading causes of mortality throughout the world. Mycobacterium tuberculosis, the agent of human tuberculosis, has developed strategies involving proteins and other compounds called virulence factors to subvert human host defences and damage and invade the human host. Among these virulence-related proteins are the Mce proteins, which are encoded in the mce1, mce2, mce3 and mce4 operons of M. tuberculosis. The expression of the mce2 operon is negatively regulated by the Mce2R transcriptional repressor. Here we evaluated the role of Mce2R during the infection of M. tuberculosis in mice and macrophages and defined the genes whose expression is in vitro regulated by this transcriptional repressor. Results We used a specialized transduction method for generating a mce2R mutant of M. tuberculosis H37Rv. Although we found equivalent replication of the MtΔmce2R mutant and the wild type strains in mouse lungs, overexpression of Mce2R in the complemented ...
We have recently reported the cloning of gyrA and gyrB genes from Mycobacterium tuberculosis H37Ra [Curr. Science, (1994) 66, 664-667). Here, we present the complete nucleotide sequence of gyrB gene from M.tuberculosis H37Ra along with the flanking regions. The gyrA gene has been located 34 nucleotides downstream of gyrB and has been partially sequenced; both the genes seem to be transcribed from the promoter elements located upstream of gyrB coding sequence. The gyrB gene encodes a polypeptide of 714 amino acids. The deduced amino acid sequences of gyrB and a part of gyrA show extensive homology to the corresponding genes from other bacterial species. The DNA gyrase of M .tuberculosis could be utilised to develop new line of antitubercular drugs.. ...
Mycobacterium tuberculosis (Mtb) causes death of 2-3 million people every year. The persistence of the pathogenic mycobacteria inside the macrophage occurs through modulation of host cell signaling which allows them, unlike the other non-pathogenic species, to survive inside the host. The secretory proteins of M. tuberculosis have gained attention in recent years both as vaccine candidates and diagnostic tools; they target the immune system and trigger a putatively protective response; however, they may also be involved in the clinical symptoms of the disease. Our studies showed that RD-1-encoded secretory protein ESAT-6 is involved in modulation of the mitogen-activated protein (MAP) kinase-signaling pathway inside the macrophage. ESAT-6 induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) in the cytoplasm but not in the nucleus, which normally is the case for MAP kinases. ESAT-6 also antagonized LPS-induced ERK1/2 phosphorylation in the nucleus. Stimulation of cells by ESAT-6
Obligate parasites Mycobacterium tuberculosis complex Contains M. tuberculosis, M. bovis, M. africanum, M. microti, M. canetti, M. caprae and M. pinnipedii Mycobacterium leprae
The Mycobacterium tuberculosis (M. tuberculosis)-specific culture filtrate protein-10 (CFP-10) is highly recognized by M. tuberculosis infected subjects. In the present study, the proliferative respon
The usage of alternative synonymous codons in Mycobacterium tuberculosis (and M. bovis) genes has been investigated. This species is a member of the high-Ci + C Gram-positive bacteria, with a genomic G + C content around 65 mol%, This G + C-richness is re. ...